The global rise in chronic, non-communicable diseases (NCDs) is inextricably linked to metabolic dysfunction, with hyperinsulinaemia acting as a potent upstream driver of ageing and age-related disease. Some of the most burdensome diseases of our time, including type 2 diabetes, cardiovascular disease, cancer, and neurodegenerative conditions, such as Alzheimer’s disease (AD), are largely underpinned by insulin resistance as part of a broader system of metabolic and mitochondrial dysfunction. These pathologies are particularly pronounced in the developed world, where obesity and other lifestyle-related conditions are major contributors to disease burden and premature mortality. As an upstream event, persistent insulin signalling biases glucose metabolism, which in turn depletes nicotinamide adenine dinucleotide (NAD+), suppresses autophagy, mitophagy and mitochondrial biogenesis, indispensable processes that maintain cellular homeodynamics. When compensatory mechanisms ultimately begin to fail, mitochondrial dysfunction and oxidative stress fuel cycles of inflammation, senescence and genomic instability. In this context, therapeutic ketosis offers an attractive strategy for metabolic restoration, with effects across insulin-dependent and downstream signalling pathways. This narrative review considers various approaches for inducing ketosis and autophagy therapeutically, including fasting, varied dietary strategies and exogenous ketogenic agents. Among these agents, ketone monoesters represent an effective and well-characterised option to rapidly elevate circulating levels of bioidentical (R)-β-hydroxybutyrate (BHB). The utilisation of BHB is fundamental to the therapeutic benefits of ketosis, functioning not only as a highly efficient mitochondrial fuel in comparison to glucose, but also a potent signalling molecule that preserves redox balance, inhibits NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, facilitates NAD+ availability, and epigenetically regulates antioxidant and repair genes. By promoting mitophagy and mitochondrial renewal, BHB may confer protection against the metabolic hallmarks of ageing, with therapeutic potential across a spectrum of diseases linked to hyperinsulinaemia. This model, articulated conceptually through the Concentric Zone Model of Adaptive Balance, proposes that restoring homeodynamics via ketosis represents a powerful strategy for metabolic correction, challenging the traditional paradigm of disease management. Under this conceptual framework, the review aims to examine the potential of therapeutic ketosis to restore metabolic flexibility, facilitate autophagy and regulate key nutrient-sensing pathways associated with ageing and disease.
Scarborough et al. (Thu,) studied this question.