In this chapter, the central role of brain glucose metabolism and its control by the neuronal insulin/insulin receptor (I/IR) signal transduction cascade is demonstrated. The normal function of I/IR signal transduction cascade is multifold. The action of acetylcholine the formation of which is controlled by insulin is directed to the microvasculature to maintain cerebral blood flow and substrate supply to the brain. The oxidative metabolism and its product ATP in particular are maintained at constant levels e.g. to ensure a pH of 6 in the endoplasmic reticulum/Golgi apparatus necessary for undisturbed protein trafficking in these intracellular compartments. In a concerted action with ATP, the I/IR signal transduction cascade supports also the APP trafficking in endoplasmic reticulum/Golgi apparatus. Likewise, it may be assumed that both ATP and insulin keep tau-protein in a state of normal phosphorylation. The effect of the I/IR signal transduction cascade in cell cycle function may be assumed to be different. I/IR stimulates processes at the S/G2/M phases of the cycle with inclusion of PI-3 kinase and MAP-kinases, and inhibits processes at the G1 phase. It is suggested that important cell functions such as protein phosphorylation are controlled/stimulated by I/IR rather than cell cycle regulation.
Functionally, the neuronal I/IR signal transduction cascade inclusive both acetylcholine and ATP contribute highly to molecular processes ensuring learning and memory capacities.
With aging, it becomes evident that multiple inherent changes in fundamental metabolic principles at the cellular, and molecular and genetic levels in cerebral glucose/energy metabolism, its control and related pathways are set into motion. Numerous changes are found to be accentuated under stress. Beside changes of single parameters, functional imbalances of regulative systems may develop such as
- energy production (reduced) and energy turnover (increased),
- insulin action (reduced) and cortisol action (increased),
- acetylcholine action (reduced) and noradrenaline action (increased), indicating a sympathetic tone,
- formation of oxidized proteins (increased) and capacity of their degradation
- shift in the gene expression profile from anabolic site (reduced) to catabolic site (increased).
These changes/shifts may indicate an uncoupling of synchronization which has been demonstrated to exist in biological systems. This model may correspond to the increase in entropy which is an elemental, inherent principle of chemical and biological processes. In the physical sciences, the term criticality is used respectively to describe a self-organized metalabile steady state (metabile equilibrium in entropy). Smaller additional internal or external events, even one that is ineffective in itself, may change biological and/or biophysical properties of the aging brain. Such events may shift a system from supercriticality to criticality to subcriticality/catastrophic reaction, i.e. a disease in medical terms.
Is the aging brain a burden of life? Even after more than 2000 years, Cicero's view is still actual. Aging in general, and aging of the brain in particular may become a burden of life for many human beings. However, although our present knowledge as to how to maintain mental capacity with aging is still limited, new findings at the cellular, molecular and genetic levels open the promising chance to meet one of the most important problems of human society: longevity with good mental health.
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