A Boundary-Centric Ontology of Disease: Entropy, Evolution, and the Primary Exchange Boundary Layer

This article proposes a boundary-centric ontology for understanding aging and chronic disease in multicellular organisms. Rather than treating late-life diseases as independent failures of organs or molecular pathways, the framework argues that many dominant pathologies of adulthood arise from declining solvency at a small number of shared physiological exchange interfaces. Drawing on thermodynamics, evolutionary biology, and classical physiology, the paper develops the concept of the Primary Exchange Boundary Layer (PEBL). This refers to the minimal set of interfaces through which organisms regulate the exchange of energy, matter, and information with their environment. In humans, this layer is instantiated primarily by the vascular intima and the alveolo-capillary membrane. These surfaces operate at steep entropy gradients, bear continuous mechanical, chemical, and inflammatory load, and are shared by all downstream tissues. Their gradual degradation under cumulative stress provides a unifying explanation for the age dependence, clustering, and resistance to late intervention characteristic of cardiovascular disease, neurodegeneration, metabolic dysfunction, frailty, and related conditions. The framework reframes regulated physiological variables such as blood pressure, glucose control, lipid flux, and autonomic tone as compensatory mechanisms designed to preserve exchange across stressed boundaries rather than as primary disease drivers. It explains why chronic disease appears late despite decades of subclinical decline, why multimorbidity is the rule rather than the exception, and why late-stage organ-specific interventions often yield limited benefit. Acute insults, including severe infection and systemic inflammation, are interpreted as rapid boundary breach events that expose preexisting reductions in exchange reserve. A central feature of the article is its explicit treatment of measurement asymmetry. While functional assessment of the alveolo-capillary membrane is well established in pulmonary physiology, no equivalent framework exists for directly measuring vascular exchange solvency. As a result, medicine relies on downstream damage markers and static thresholds, leading to systematic delay in detection. The paper outlines how dynamic testing under load, recovery kinetics, and variability-based metrics could better align measurement with the proposed ontology. The article does not introduce new biomarkers, therapeutic classes, or claims of dramatic life extension. It is offered as an organizing framework intended to reorder existing knowledge, clarify the limits of current prevention strategies, and generate testable hypotheses regarding early intervention, recovery dynamics, and healthspan preservation. Its scope is restricted to adult, time-dependent chronic disease in multicellular organisms and explicitly excludes pediatric, congenital, monogenic, and purely stochastic pathologies. Overall, the work aims to provide a coherent causal structure linking thermodynamic constraint, evolutionary architecture, physiological regulation, disease emergence, and health economics, while remaining agnostic about specific implementation details pending the development of boundary-appropriate measurement tools.