Ketogenic Diet, Aging, and Neurodegeneration

Abstract

AbstractThe brain, unlike other organs, is normally completely dependent on glucose, but is capable of using ketones as an alternate energy source, as occurs with prolonged starvation or chronic feeding of a ketogenic diet (high fat, low carbohydrate). Over the past decade, research has consistently shown that ketosis is neuroprotective against ischemic insults in rodents. This chapter focuses on investigation of the mechanistic links to neuroprotection by ketosis in the aged. Recovery from stroke and other pathophysiologic conditions in the aged is challenging. Cerebral metabolic rate for glucose (CMRglu), cerebral blood flow (CBF), and/or the defenses against oxidative stress are known to decline with age, suggesting dysfunction of the neurovascular unit. One mechanism of neuroprotection by ketosis involves succinate-induced stabilization of hypoxia-inducible factor 1α (HIF-1α) and its downstream effects on intermediary metabolism. It is possible that ketone bodies play a role in the restoration of energy balance (stabilization of ATP supply), as well as act as signaling molecules, through the upregulation of anti-inflammatory and prosurvival pathways targeted by HIF-1α.