From Regime Alteration to Inflammaging: When Feedback Changes the System

Aging is accompanied by changes in the biological systems responsible for maintaining coordinated function, regulating disturbances, and restoring stability. These changes can produce a fundamental therapeutic problem: an intervention that engages its intended molecular target may nevertheless fail to restore function, lose effectiveness, or produce an entirely different consequence as the organism ages. This preprint examines that problem through inflammaging, the persistent, heterogeneous inflammatory condition associated with aging, and develops a framework for distinguishing four causal architectures that may explain altered intervention outcomes: Continuing burden or failed termination, in which persistent stimuli, damage, or impaired resolution maintain inflammatory activity. Reciprocal feedback, in which interacting biological processes sustain or amplify pathological activity without necessarily changing the underlying regulatory organization. Durable recalibration, in which biological history produces lasting changes in response thresholds, regulatory gains, cellular composition, timing, or coupling. Persistent regime alteration, in which such changes become integrated into a higher-order organization that conditions the subsequent behavior of multiple interacting physiological systems. The paper examines experimental and clinical evidence involving age-dependent intervention response, late-life metformin toxicity, acquired cancer treatment resistance, mTOR inhibition, and inflammatory-targeting therapies. These examples demonstrate why successful pathway engagement, biomarker normalization, and restoration of organism-level function cannot be treated as equivalent outcomes. Inflammaging is investigated as a candidate manifestation of higher-order regime alteration because immune regulation is closely coupled to metabolism, cellular senescence, tissue repair, vascular function, barrier integrity, proteostasis, and other stability-maintaining processes. The paper does not presume that inflammaging constitutes an established organism-level regime alteration. Instead, it identifies the additional evidence needed to distinguish that hypothesis from simpler explanations. The framework has important implications for therapeutic development. Treatment effectiveness may depend on the biological organization receiving an intervention, the patient's prior biological and treatment history, and the sequence in which interventions are applied. Correcting an individual molecular target may be insufficient if the surrounding organization cannot sustain the resulting improvement. To make these distinctions experimentally testable, the paper proposes state-matched perturbation studies, treatment withdrawal and rechallenge, intervention-sequence comparisons, standardized challenges following apparent normalization, and cross-system recovery measurements. Part of the broader Stability Biology research programme, this work advances a systems-level approach to aging and age-related disease in which therapeutic strategy depends not only on identifying what should be changed, but also on understanding the regulatory organization in which that change must become effective and sustainable. This paper provides the Explanation stage of a four-paper Stability Biology programme progressing from Observation to Explanation to Representation to Navigation.