Declining Energy Metabolism in the Aging Brain
This open access paper argues for the importance of mitochondrial dysfunction in the brain to the onset of neurodegenerative conditions. The primary function of mitochondria, a herd of these bacteria-like organelles found in every cell, is the production of adenosine triphosphate (ATP), a chemical energy store molecule. The energy stored in ATP is used to power cellular operations. It is thus vital in every tissue, but particularly so in the most energy-hungry tissues, such as brain and muscle.
With advancing age, mitochondria become dysfunctional throughout the body, and ATP production falters as a consequence. A network of interacting contributing causes is involved, such as loss of NAD, changes in gene expression that cause quality control mechanism of mitophagy responsible for removing worn and damaged mitochondria, and damage to mitochondrial DNA. Effective means of addressing age-related mitochondrial dysfunction is an important topic in rejuvenation research.
There is a growing body of evidence that indicates that the aging of the brain results from the decline of energy metabolism. In particular, the neuronal metabolism of glucose declines steadily, resulting in a growing deficit of adenosine triphosphate (ATP) production - which, in turn, limits glucose access. This vicious circle of energy metabolism at the cellular level is evoked by a rising deficiency of nicotinamide adenine dinucleotide (NAD) in the mitochondrial salvage pathway and subsequent impairment of the Krebs cycle. A decreasing NAD level also impoverishes the activity of NAD-dependent enzymes that augments genetic errors and initiate processes of neuronal degeneration and death.
This sequence of events is characteristic of several brain structures in which neurons have the highest energy metabolism. Neurons of the cerebral cortex and basal ganglia with long unmyelinated axons and these with numerous synaptic junctions are particularly prone to senescence and neurodegeneration. Unfortunately, functional deficits of neurodegeneration are initially well-compensated, therefore, clinical symptoms are recognized too late when the damages to the brain structures are already irreversible. Therefore, future treatment strategies in neurodegenerative disorders should focus on energy metabolism and compensation age-related NAD deficit in neurons.