Neuro-Metabolic Ageing Drives Diabetes-Associated Neurodegeneration: A Geroscience and Network Pharmacology Perspective.
TL;DR
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.
Abstract
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.