A shared stress-inflammation signalling architecture underlying chronic disease and multimorbidity.

Abstract

Chronic non-communicable diseases are conventionally classified as distinct clinical entities, yet multimorbidity has become the dominant phenotype in modern populations. Converging experimental, clinical and epidemiological evidence indicates that metabolic overload-characterised by persistent hyperinsulinaemia, insulin resistance and nutrient-driven anabolic signalling-acts as a central amplifier of conserved stress-response systems and chronic low-grade inflammatory signalling. Under contemporary exposome conditions, sustained metabolic stress chronically engages sympathetic and renin-angiotensin-aldosterone signalling, oxidative stress pathways and innate immune activation, establishing a tightly coupled feed-forward network that stabilises pathological states across organ systems. Here, I synthesise mechanistic data from endocrinology, immunometabolism, vascular biology and ageing research to propose a unified stress-signalling architecture linking systemic stress axes to shared intracellular integration hubs. These include inflammatory transcriptional regulators (NF-κB, AP-1), stress-activated kinases (MAPKs), and nutrient- and oxygen-sensing pathways centred on PI3K-Akt-mTOR and HIF-1α, with additional modulation by Notch signalling. When cytoprotective buffering and stress-resolution mechanisms-particularly NRF2 activity, autophagy and mitochondrial resilience-are insufficient, persistent activation of these hubs enforces inflammatory tone, metabolic inflexibility, impaired proteostasis and maladaptive tissue remodelling, providing a mechanistic explanation for phenotypic convergence across cardiometabolic, inflammatory, degenerative and hyperplastic diseases. Importantly, epidemiological and anthropological observations indicate that multimorbidity is not an inevitable consequence of ageing per se, but instead reflects environmentally contingent persistence of stress-response programmes rather than intrinsic ageing trajectories. Framing chronic disease through this integrated metabolic-stress signalling architecture positions multimorbidity as a mismatch phenotype rather than a programmed endpoint of human longevity, and highlights upstream stress regulation and restoration of metabolic resilience as central targets for system-level prevention and intervention.