Supplying the Aging Brain with More Energy

A growing dysfunction in energy metabolism, such as might be caused by higher levels of mitochondrial damage in cells, has been implicated in the progression of age-related neurodegenerative conditions. The neurons of the brain collectively require a lot of energy to operate, and thus it is reasonable to consider that disruptions in the processes that provide that energy are significant. Such disruptions are not the root causes of neurodegeneration, however, but rather secondary or later effects of an accumulation of the fundamental cell and tissue damage that causes aging. One possible compensatory approach to therapy, a treatment that doesn't address the root causes but instead tries to modestly slow down their consequences, would involve delivering more energy stores to neurons. The researchers here report on a fairly simple proof of concept in mice:

The human brain has a prodigious demand for energy - 20 to 30% of the body's energy budget. In the course of normal aging, in people with neurodegenerative diseases or mental disorders, or in periods of physiological stress, the supply of sugars to the brain may be reduced. This leads to a reduction in the brain's energy reserves, which in turn can lead to cognitive decline and loss of memory. But new research on mice shows that the brain's energy reserves can be increased with a daily dose of pyruvate, a small energy-rich molecule that sits at the hub of most of the energy pathways inside the cell. These results need to be replicated in human subjects, but could ultimately lead to clinical applications.

"In our new study, we show that long-term dietary supplementation with pyruvate increases the energy reserves in the brain, at least in mice, in the form of the molecules glycogen, creatine, and lactate. The mice became more energetic and increased their explorative activity. It appears that these behavioral changes are directly due to the effect of pyruvate on brain function, since we didn't find that these mice had developed greater muscle force or endurance. For example, chronic supplementation with pyruvate facilitated the spatial learning of middle-aged (6- to 12-months-old) mice, made them more interested in the odor of unfamiliar mice, and stimulated them to perform so-called "rearing", an exploratory behavior where mice stand on their hind legs and investigate their surroundings. The dose necessary to achieve these effects was about 800 mg pyruvate per day - which corresponds to about 10 g per day in humans - given to the mice in normal chow over a period of 2.5 to 6 months. A single large dose of pyruvate injected directly into the blood stream had no detectable effect.



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