Neuro-Metabolic Ageing Drives Diabetes-Associated Neurodegeneration: A Geroscience and Network Pharmacology Perspective.
Ageing destabilizes metabolic and neuronal regulatory networks, increasing vulnerability to type 2 diabetes (T2D) and neurodegenerative disorders. These conditions are not independent disease entities but interconnected manifestations of accelerated neuro-metabolic ageing, driven by convergent impairments in insulin signaling, nutrient sensing, mitochondrial bioenergetics, redox homeostasis, proteostasis, and chronic inflammation - processes mediated through conserved hubs including AMPK, mTOR, SIRT1, GSK3β, and NF-κB. Therapeutic strategies targeting isolated molecular lesions or late-stage pathology have consequently shown limited success in preserving cognitive and metabolic function. With T2D projected to affect 643 million people by 2030, this review adopts a geroscience framework to examine the neuro-metabolic axis as a systems-level ageing process. By integrating mechanistic insights, network pharmacology, and translational evidence, it highlights how ageing-associated network collapse drives the reciprocal reinforcement of metabolic dysfunction and neurodegeneration. Within this context, phytochemicals are repositioned not as alternative therapeutics but as biologically informative multi-node modulators illustrating the feasibility of stabilizing ageing-regulatory networks through coordinated pathway engagement. Experimental and clinical evidence indicates that phytochemicals engage conserved ageing hubs spanning insulin-IGF signaling, AMPK-mTOR nutrient sensing, redox regulation, and mitochondrial quality control - exemplified by berberine via AMPK, curcumin via NF-κB, and resveratrol via SIRT1. Translational impact remains variable, reflecting constraints of bioavailability, pharmacokinetics, and clinical heterogeneity, underscoring the need for ageing-aware models and stratified trial designs. Collectively, this review reframes diabetes-associated neurodegeneration as a consequence of neuro-metabolic ageing and argues that effective intervention must prioritize preservation of network resilience over correction of isolated disease endpoints. Aligning therapeutic strategies with the biology of ageing itself offers a more realistic pathway toward sustaining metabolic flexibility, neuronal integrity, and cognitive health across the ageing trajectory.