Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer's disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes—both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering β-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing β-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing β-amyloid degradation. 1. Introduction Aging can be defined as a process that invariably causes a decline in the abilities of the individuals to face environmental stressors, leading to a dysfunction in homeostasis and an increased incidence of chronic degenerative diseases [1]. Cognitive decline, which is an important aspect of aging, is a leading cause of morbidity and mortality among the elderly, since it greatly impairs their activities of daily living and quality of life [2]. Some patterns of neurodegeneration involved in cognitive impairment are highly preserved phylogenetically in mammals—such as reduced synaptic activity in neurons, alterations in glial metabolism, and accumulation of specific metabolic products [3]. In this chapter we will review the relationships between some disorders of metabolism related to insulin dysfunction and cognitive decline and the importance of these alterations to the neurodegenerative process in aging-related disorders, particularly Alzheimer’s disease. 2. Interactions between Aging and Insulin Regulation The ultimate cause of senescence remains unknown. However, Some specific mechanisms possess major roles in regulating the aging process [4, 5]. Presently, reconciliation between the two main theories of aging would be the proposal that the cumulative effects of the Reactive Oxygen Species (ROS) and Advanced Glycation End products (AGE) leads to aging. In another
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