Aging as the degradation of conjunctive coupling: A triadic framework S = F × E × N for biological senescence.

Abstract

Despite the landmark identification of twelve hallmarks of aging (López-Otín et al., 2023), geroscience lacks a formal account of why these hallmarks interact and amplify each other, why mono-target interventions show systematically limited efficacy, and what determines the threshold at which compensatory mechanisms fail. A recent extension of the hallmarks framework has further integrated psychosocial and social determinants of aging (López-Otín & Kroemer, 2025; Kroemer et al., 2025), reinforcing the need for an architectural account that can accommodate both molecular and environmental modulators within a single formal structure. The hallmarks framework, in its current form, remains descriptively comprehensive but architecturally silent: it documents what accumulates without specifying why the regulatory system that normally contains these accumulations progressively loses coherence. This article proposes a minimal architectural framework - S = F × E × N - in which F designates the flux of biological signals (genomic, epigenetic, metabolic, intercellular), E the executive and energetic machinery (mitochondrial function, proteostasis, autophagy), and N the normative epigenetic constraint (chromatin architecture, DNA methylation landscape, cell identity program). The × operator denotes conjunctive necessity: stable organized biological state S exists only when F, E, and N are simultaneously coupled and functional. The central contribution is a specific architectural claim: aging is not primarily the degradation of F, E, or N individually, but the progressive erosion of the × operator - the conjunctive coupling that maintains their coherent interaction. Within this framework, N occupies a structurally asymmetric position: as the normative anchor that governs the F→E transaction, N erosion is sufficient to collapse × even when F and E remain intact. This asymmetry - not N-primacy as an independent thesis - explains why Yang et al. (2023a) found that epigenetic information loss alone reproduces full aging phenotypes and that OSK-mediated N restoration reverses them. The pathological unit remains × ; N is the component through which × is most vulnerable to disruption and most tractable for therapeutic intervention. Formalized within Partial Information Decomposition theory as the synergistic information I_synergistic(F,E,N), × erosion is in principle computable on multi-omic data using established PID estimators and is directly falsifiable. The framework predicts why hallmarks accelerate each other (conjunctive failure propagates across components), why mono-target interventions fail (restoring one component does not restore the coupling), and why combined N + E interventions should produce superadditive healthspan effects. Three priority testable predictions and a CouplingIndex measurement pipeline are derived.