Aging research has identified recurring mechanisms but still lacks a ranked causal architecture. We argue that aging is best understood as progressive loss of biological fidelity across genome maintenance, epigenetic and chromatin organization, proteome quality control, organelle coordination, and multicellular signaling. Conserved nutrient- and stress-sensing pathways such as IIS–mTOR–FOXO regulate the pace of this loss rather than serving as its sole origin. As fidelity declines, protective responses including senescence and inflammatory signaling become chronic, while amplifier loops—including inflammaging, clonal hematopoiesis, dysbiosis, neuroendocrine-circulatory coupling, and tissue-mechanical drift—spread local failures into organism-wide state change. Tissue-specific executor modules then produce stem-cell exhaustion, cell-identity drift, and organ-specific decline. This ranked model explains more than flatter alternatives that treat hallmarks as co-equal lesions or equate clocks with mechanism. It also predicts that early shared changes will arise in chromatin state, proteostasis, and organelle communication, and that state-restoring interventions will improve clocks and function more readily than deep structural lesions.
Harry Negron (Fri,) studied this question.