Network Destabilization in Aging: Mitochondrial Dysfunction, Nutrient Sensing, and Chronic Inflammation as Interconnected Drivers

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.

Mitochondrial Dysfunction as a Central Hub of Aging: From Molecular Cascades to Inter-Organ Communication Networks.

This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming, and critically examines how mitochondria act as signaling hubs for inter-organ crosstalk.

Cardiovascular Diseases and Cancer: Convergent Proteostasis Networks at the Crossroads of Mechanisms and Therapeutic Opportunities

Cancer and cardiovascular diseases, the primary causes of mortality globally, are increasingly understood as biologically interconnected rather than distinct pathologies. Recent evidence indicates that protein homeostasis (proteostasis) functions as a crucial molecular link connecting tumor progression, therapeutic resistance, cardiac remodeling, and treatment‐related cardiotoxicity. Proteostasis, which encompasses the cellular processes of protein synthesis, folding, quality control, and degradation, dictates tissue adaptation to chronic stress. Notably, the adaptive mechanisms that allow tumor cells to endure proteotoxic stress and resist therapy are often vital for maintaining cardiac structure and function. Thus, tumor control and cardiovascular injury may be divergent outcomes of a common stress–response framework. In this review, we propose proteostasis as a comprehensive framework for understanding the cancer–cardiovascular interface. We analyze how the ubiquitin–proteasome system, autophagy–lysosome pathway, endoplasmic reticulum stress‐induced unfolded protein response signaling, and molecular chaperone networks are differentially reconfigured in cancer and cardiac tissues, influencing tumor survival, therapeutic susceptibility, and cardiovascular dysfunction. Additionally, we explore the translational implications of proteostasis dysregulation, including mechanisms of anticancer therapy‐induced cardiotoxicity, emerging biomarkers, cardioprotective strategies, and opportunities for precision cardio‐oncology. By conceptualizing efficacy and toxicity as interconnected outcomes of shared proteostasis biology, this review establishes a foundation for developing therapies that optimize cancer control while safeguarding cardiovascular health.

To longevity and beyond: a systems view of aging and stress resilience.

Mitochondrial-Centered Biological Networks in Metabolic Disease: Toward Precision Mitochondrial Medicine

Obesity and type 2 diabetes (T2D) are multifactorial metabolic disorders characterized by progressive dysfunction of multiple organs and biological systems. Although mitochondrial dysfunction is a hallmark of disease progression, the mechanisms linking metabolic stress to coordinated tissue dysfunction remain incompletely understood. Comparative proteomic studies have consistently identified coordinated remodeling of oxidative phosphorylation, fatty acid oxidation, tricarboxylic acid cycle activity, redox regulation, mitochondrial proteostasis, and adaptive signaling across metabolically affected organs, revealing conserved organizational principles underlying mitochondrial adaptation. However, these findings have largely been interpreted within reductionist, pathway-centered frameworks. Here, we integrate evidence from comparative proteomics, mitochondrial biology, bioenergetics, redox biology, signaling, and systems biology to propose the concept of mitochondrial-centered biological networks (MCBNs), in which mitochondria function as dynamic regulatory hubs coordinating interconnected processes that collectively determine metabolic adaptation and tissue resilience. Building on this framework, we introduce the Mitochondrial Homeostasis Hypothesis, which proposes that preservation or restoration of mitochondrial homeostasis depends on coordinated regulation of MCBNs and constitutes a fundamental systems-level mechanism underlying resistance to obesity, T2D, and hypercaloric diet-induced metabolic dysfunction. Curcumin represents a well-studied network-modulating intervention that coordinately influences mitochondrial bioenergetics, metabolic flexibility, redox homeostasis, proteostasis, inflammatory signaling, and adaptive stress responses, supporting the concept that mitochondrial homeostasis is preserved through coordinated network regulation rather than isolated modulation of individual molecular pathways. Finally, we discuss how emerging technologies, including functional proteomics, redox proteomics, spatial and single-cell proteomics, acetylomics, integrated multi-omics, and artificial intelligence-assisted network analysis, provide unprecedented opportunities to quantitatively characterize MCBNs, validate the proposed hypothesis, identify network-based biomarkers, and accelerate the development of network-guided precision mitochondrial medicine.

The PERK paradox in aging: how ER stress shapes senescence and neurodegeneration.