The dramatic rise in the number and proportion of older persons since the beginning of this century has forced attention on research into aging and has encouraged the search for new forms of health service delivery to older persons. Human aging trajectories are very heterogeneous. To study mechanisms that may underlie this heterogeneity, several models of aging have been proposed in humans (Akintola and van Heemst, 2015). For example, obesity with its associated increased insulin resistance and increased risk for a multitude of age-related diseases is seen as a model for accelerated aging (Hu et al., 2004). Due to the combination of long-term exposure to nutrient excess and a sedentary lifestyle, the prevalence of obesity has escalated worldwide. On the other hand, preserved sensitivity to insulin has been associated with longevity in humans. Stemming from research in nematodes, fruit flies, and mice, insulin and insulin-like growth factor-1 (IGF-1) signaling were shown to play a key role in the sensing and responding to the environment and have been implicated in extension of life span. Insulin, IGF-1, and their receptors are involved in signaling pathways that have major impact on aging and longevity in model organisms, mammals, and humans. In model organisms, such as Caenorhabditis elegans and Drosophila, neural manipulations of insulin or IGF-1 signaling were shown to affect life span and have been consistently linked to longevity. Interestingly, long-lived growth hormone-deficient dwarf mice display an enhanced insulin sensitivity and very low circulating levels of IGF-1, while brain IGF-1 levels were elevated (Sun et al., 2005). In mice, several data strongly suggest that a combination of reduced circulating insulin levels and the augmentation of insulin sensitivity is critical for longevity extension. For example, fat-specific insulin receptor knockout mice were shown to be long-lived and protected against diet-induced obesity (Bluher et al., 2003). In exceptionally long-lived humans, longevity has also been linked to preserved insulin sensitivity. Centenarians exhibit protection against the decline in insulin resistance that is associated with aging, as demonstrated by preserved insulin levels and favorable insulin sensitivity (Paolisso et al., 1996). Furthermore, it has been shown that offspring of long-lived nonagenarian siblings displayed lower circulating levels of glucose, slightly lower circulating insulin levels and enhanced peripheral insulin sensitivity (Rozing et al., 2009; Wijsman et al., 2012), lower prevalence of metabolic syndrome and diabetes, and decreased mortality risk. Thus, insulin sensitivity, low insulin, and low glucose are key metabolic features of human aging and longevity. Homeostatic control of glucose is via various mechanisms, namely via pancreatic islet control and brain control of glucose homeostasis (Akintola et al., 2015). These homeostatic circuits are disrupted in disease states such as diabetes mellitus (DM) and with aging. In this chapter, we will summarize recent findings concerning mechanisms and novel mediators of insulin action in the brain and how these are affected by aging.
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