Function and treatment strategies of β-hydroxybutyrate in aging

Metabolic intermediates serve as precursors for bioactive molecule synthesis, the energy source for life activities, and signals for environmental adaptation. Ketone bodies are important metabolic intermediates produced in the liver by the degradation of fatty acids, acting as an alternative energy source for extrahepatic tissues when glucose is short in supply (especially during starvation). β-hydroxybutyric acid, with its conjugate base β-hydroxybutyrate, constitutes approximately 70% of ketone bodies. A growing number of studies have demonstrated the beneficial effects of β-hydroxybutyrate, especially in delaying aging, intervening in aging-related disease, and promoting longevity. This review systematically reviews the role of β-hydroxybutyrate in aging hallmarks, shedding light on the possible molecular mechanism by which β-hydroxybutyrate supports healthy aging. Higher circulating β-hydroxybutyrate can be achieved by lifestyle modification (ketogenic diet or caloric restriction) or exogenous β-hydroxybutyrate (or β-hydroxybutyrate precursors, derivates and agonists) supplementation. We will also discuss the pros and cons of different ways to upregulate β-hydroxybutyrate, emphasizing the promising future clinical use of poly-β-hydroxybutyrate, the polymers of β-hydroxybutyrate, which can be easily produced via a microbial platform and synthetic biology.