Is Aging a Failure to Resolve? Integrating Damage Responses, Regenerative Decline, and Geroscience Interventions

Abstract

Biological aging is accompanied by persistent tissue-damage signaling, chronic inflammation, extracellular matrix remodeling, cellular senescence, and declining regenerative capacity. Taken together, these features resemble an injury response that is repeatedly initiated but fails to progress reliably through clearance, reconstruction, and functional recovery. This resemblance motivated the proposal that aging is a wound that never starts healing. Here, we develop that proposal into a testable failed-resolution framework in which some age-related dysfunction reflects damage responses that exceed organ-specific capacities for intracellular quality control, efferocytosis, immune termination, matrix normalization, and cell replacement. Its central predictions are that (i) impaired recovery kinetics will forecast functional decline beyond established measures of biological age, (ii) restoring resolution will improve tissue function beyond suppressing inflammatory markers, and (iii) efficacy will depend on treatment phase and tissue-specific failure mode. We specify which age-related processes lie outside the framework and propose measurements spanning damage burden, danger sensing, resolution competence, regenerative reserve, organ function, and recovery after standardized challenge. Supporting evidence is predominantly preclinical, whereas human studies provide mechanistic findings, target engagement, or domain-specific effects. Failed resolution thus offers a falsifiable research program for testing tissue recovery as a therapeutic target in aging.

The authors' abstract, as published at the source. International Journal of Molecular Sciences, 2026 · DOI ↗