The metabolite alpha-ketobutyrate increases health and life spans by activating AMPK

Aging is a complex process that is directly related to human health and disease. The extraordinary finding that aging is malleable, as shown in model organisms whose life and health spans are extended by specific gene mutations or dietary or pharmacological perturbations, has offered enormous hope for our understanding and treatment of aging and related diseases. Although many molecules have been identified that can extend the lifespan of model organisms, few have been shown to alleviate age-related symptoms or illness in mammals. Here we show that supplementation with the endogenous metabolite alpha-ketobutyrate (alpha-KB) increases the lifespan of adult C. elegans. Using Gelfree DARTS-PROTOMAP, we identified microtubule-actin cross-linking factor (MACF1) that was protected against proteolysis in the presence of alpha-KB. MACF1 belongs to the spectraplakin family of giant, evolutionarily conserved proteins with versatile functions, but their link to longevity regulation has not been explored. Alpha-KB longevity effect in C. elegans is abrogated by loss-of-function mutation in vab-10, encoding the worm ortholog of mammalian MACF1. Like alpha-KB treatment, vab-10 knockdown activates AMP-activated protein kinase (AMPK), and AMPK is required for alpha-KB effects on longevity. The findings suggest a model in which alpha-KB increases longevity by activating AMPK via VAB-10/MACF1 modulation. Alpha-KB also delays aging in mammals, increasing the lifespan of aged male mice and the healthspan of both male and female animals. Targeting of broadly expressed scaffolding proteins in connection to cellular energy homeostasis seems to be a clever way that nature has devised for metabolite signals to impinge upon multiple organ and tissue systems, which may have utility for controlling aging and related diseases. ### Competing Interest Statement UCLA has filed patent applications on the basis of this work, on which C.C., B.L., M.C., W.H., J.C., L.V., R.M.C., X.F., H.H., X.Y., M.J., K.R., and J.H. are named as inventors. J.H. is a founder and scientific advisory board member of LongLifeRx and Aiance.