The Role of Brain Lactate Metabolism in Neuroprotection During Healthy Aging

The human brain has an immense energy demand that is fueled almost exclusively by glucose. Unfortunately, the brain's ability to metabolize glucose declines with age, and this is linked to neurodegenerative diseases. Finding ways to delay, halt, or reverse brain glucose hypo-metabolism is fundamental to promoting healthy brain aging. Exercise is a well-established way to improve brain glucose metabolism. The investigators have discovered a mechanism through exercise to selectively upregulate aerobic glycolysis - the specific pathway that is responsible for the age-related decline in whole brain glucose metabolism. Aerobic glycolysis is a unique form of glucose metabolism that does not undergo oxidative phosphorylation despite sufficient oxygen availability, and is essential during brain activation, learning, and memory formation, and is highest in the early stages of life when synaptic plasticity and growth are occurring at rapid rates. Preserving aerobic glycolysis during aging protects against Alzheimer's disease. The investigators have developed an experimental model that reproducibly upregulates aerobic glycolysis in a controlled manner using infusion of lactate - an alternative and preferred fuel for the brain. Whether lactate is increased passively via infusion, or actively via exercise, aerobic glycolysis is promoted, indicating that lactate may well be the key to activating brain aerobic glycolysis during exercise. The investigators objective is to exploit this unique role of lactate to evaluate changes in brain metabolism during healthy aging. The specific aims are to test whether aerobic glycolysis can be upregulated via lactate similarly in young and older healthy individuals and determine if age influences the neurotrophic and cognitive benefits afforded by lactate in young adults. The approach is to combine our invasive cross-brain blood sampling technique with stable isotope tracers to directly quantify brain substrate metabolism during exercise and lactate infusion in healthy young adults (aged 20-30) and healthy older adults (aged 65-80). This contribution is significant since aerobic glycolysis is a metabolic signature of a young, resilient brain. Identifying ways to naturally upregulate aerobic glycolysis throughout the lifespan will provide a framework to build therapies targeted toward healthy brain aging.

The general purpose is to characterize brain metabolism during healthy aging. The investigators will do this by directly assessing brain fuel metabolism in young and older humans in response to two interventions: 1) exercise, and 2) lactate infusion, both of which challenge the brain to use alternative fuels. It is hypothesized that: 1) when made available to the brain, lactate will spare glucose for aerobic glycolysis (a beneficial metabolic pathway) and stimulate the production of neurotrophic factors in the brain, and 2) that this metabolic 'flexibility' to upregulate aerobic glycolysis will be preserved in healthy aging. Generally, the investigators will test if this youthful pattern of aerobic glycolysis can be resurrected late in life through acute exercise. The specific aims are:

1. Determine if increasing circulating lactate - passively via infusion and actively via exercise - translates to increased brain lactate metabolism equally in otherwise healthy young and elderly humans, i.e., brain is metabolic flexibility preserved across the lifespan?
2. Verify that increasing brain lactate metabolism causes a proportional decrease in glucose oxidation, thus providing evidence for a glucose-sparing effect of lactate, and;
3. Determine if lactate causes a similar neurotrophic and cognitive effect in healthy young and elderly humans, i.e., does exercise permit the same brain benefits throughout the lifespan?