Aging is intimately related to health and disease. The incidence of major fatal pathological conditions, including cancer, is strongly associated with aging. The finding that aging is malleable by genetic or pharmacological perturbations has offered enormous hope for transforming our understanding and treatment of aging and age-related diseases. Yet few valid longevity drugs have been developed or translated for treating age-related diseases as target identification and a mechanistic understanding of their activity is largely missing.
Metabolism plays a pivotal role in aging. Metabolic interventions, such as dietary restriction, significantly modulate aging and aging-related symptoms. Recently, emerging evidences has shown that metabolites can directly modulate aging as well. Studies of these endogenous “elixirs” provide insights on the biological regulatory networks acted upon by the metabolites as well as potential therapeutic interventions for aging and aging-related symptoms.
Our lab aims to discover novel longevity metabolites and explore their applications in aging-related symptoms. Here we present several novel longevity metabolites, which are α-ketoglutarate (α-KG), 2-hydroxyglutarate (2-HG), and α-ketobutyrate (α-KB). By combining target identification, epistasis, metabolomics, and bioenergetics analyses, we successfully uncover the molecular mechanisms of the longevity effects of these compounds. Specifically, we, for the first time, showed that α-KG and 2-HG extend lifespan of C. elegans by inhibiting ATP synthase and TOR, while α-KB delays aging through interruption of pyruvate oxidation and activation of AMPK. Interestingly, we discover an unexpected growth inhibitory effects of α-KG and 2-HG on tumor cells through targeting ATP synthase, and find that α-KG may confer beneficial effects for tumor treatment. In brief, our results identify novel potent longevity compounds and reveal their underlying mechanisms. More importantly, our work suggests a potential translational application of longevity metabolites in aging-related symptoms and provides novel directions for metabolic therapy.