Ketone bodies, potential therapeutic uses

Ketosis, meaning elevation of D-beta -hydroxybutyrate (R-3-hydroxybutyrate) and acetoacetate, has been central to starving man's survival by providing nonglucose substrate to his evolutionarily hypertrophied brain, sparing mu scle from destruction for glucose synthesis. Surprisingly, D-beta -hydroxyb utyrate (abbreviated "beta OHB") may also provide a more efficient source o f energy for brain per unit oxygen, supported by the same phenomenon noted in the isolated working perfused rat heart and in sperm. It has also been s hown to decrease cell death in two human neuronal cultures, one a model of Alzheimer's and the other of Parkinson's disease. These observations raise the possibility that a number of neurologic disorders, genetic and acquired , might benefit by ketosis. Other beneficial effects from beta OHB include an increased energy of ATP hydrolysis (AG) and its linked ionic gradients. This maybe significant in drug-resistant epilepsy and in injury and anoxic states. The ability of beta OHB to oxidize co-enzyme Q and reduce NADP(+) m ay also be important in decreasing free radical damage. Clinical maneuvers for increasing blood levels of beta OHB to 2-5 mmol may require synthetic e sters or polymers of beta OHB taken orally, probably 100 to 150 g or more d aily. This necessitates advances in food-science technology to provide at l east enough orally acceptable synthetic material for animal and possibly su bsequent clinical testing. The other major need is to bring the technology for the analysis of multiple metabolic "phenotypes" up to the level of soph istication of the instrumentation used, for example, in gene science or in structural biology. This technical strategy will be critical to the charact erization of polygenic disorders by enhancing the knowledge gained from gen e analysis and from the subsequent steps and modifications of the protein p roducts themselves.