Is Immune Homeostatic Competence a Distinct Capacity? A Falsifiable Test for a Sixth Determinant of Functional Reserve
Year: 2026
Type: preprint
Abstract: A functional reserve framework for human aging proposed five modifiable physiological capacities organized around a coupled mitochondrial—epigenetic axis and excluded immune competence because its major age-related failures were interpreted as mediated through the other capacities. The exclusion now deserves formal reopening. Immune resilience is established as a predictor of survival and of physical recovery; whether it is a capacity, distinct from the framework's existing adaptive stress response, is not. Chronic inflammation should not be promoted to a determinant: inflammaging is a state, not a capacity, and its biomarkers do not specify the system that failed. Yet it is also not merely an output. Human longitudinal studies, immune-age trajectories, clonal hematopoiesis, Mendelian randomization, and experimental perturbation show that immune dysfunction can arise through partially autonomous mechanisms and feed back to accelerate neural, vascular, metabolic, regenerative, and mitochondrial injury. I define immune homeostatic competence as the capacity to mount a proportionate defense, terminate that response, clear its residue, and reconstitute effective immune architecture after challenge. Under the framework's conjunctive admission rule, this candidate provisionally satisfies necessity and modifiability and may satisfy independence, but only if it adds information beyond the existing adaptive stress response determinant. That boundary—not the importance of inflammation—is the decisive test. A secondary, multilayer network analysis using an open 524,156-edge human interactome, public hallmark assignments, transcriptomic resources, perturbation signatures, genetic summary statistics, and controlled-access aging cohorts can adjudicate both the proposed sixth
Author: O'Leary, Robert T.
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7212351325
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