CYTOSKELETON Microtubules Microfilaments Neurofilaments Mitosis Growth cones Axons and dendrites Synaptic terminals Neural stem cells Neurons Astrocytes Oligodendrocytes AGING DISEASE Oxidative stress Metabolic stress Altered ion homeostasis Impaired neurogenesis Synaptic dysfunction Cell death

This chapter provides developmental neurobiologists with an overview of cellular and molecular changes that occur in the nervous system during aging, describes the current state of understanding of how aging impacts developmental processes operative in the adult nervous system, and considers how developmental mechanisms may contribute to the pathogenesis of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Although studies of invertebrates, particularly Caenorhabditis elegans and Drosophila, have provided vital information on the molecular regulation of development, they have not yet been tapped to study mechanisms of nervous system aging. This chapter, therefore, focuses almost exclusively on the aging of mammalian nervous systems. While many ageassociated changes in the nervous system also occur in other tissues, we will focus on those that have the highest impact (such as oxidative stress and protein accumulation) and those that are relatively unique to the nervous system (such as the age-associated alterations in the Notch–Delta signaling pathway). We will then explore some of the mechanisms that not only regulate development of the nervous system, but also play a role in aging in both the normal and diseased brain. We now know that a spectrum of developmental processes operates in the adult mammalian nervous system. The adult nervous system is not “hard-wired”; instead, neuronal circuits undergo structural remodeling in response to environmental demands. Like other tissues, there are cells in the nervous system capable of undergoing proliferation, differentiation, and programmed cell death (apoptosis), as well as a number of more subtle changes that alter neural structure and function. For example, hippocampal synapses may form, disassemble, or change their shape in response to learning, stress, and fluctuations in levels of sex steroids (McEwen, 2001). In neurogenic regions of the adult brain, there are dynamic populations of stem cells capable of dividing and differentiating into neurons or glial cells (Gage, 2000). Programmed cell death (apoptosis) also occurs in the adult nervous system, at a low level under normal conditions, and at an accelerated pace following injury or in certain neurological disorders (Mattson, 2000). As far as is known, developmental processes in the mature nervous system are regulated by similar, if not identical, signaling mechanisms to those employed during embryonic development. Thus, members of each of the major types of signaling systems employed in embryonic development are operative in the adult. The impact of aging on these signaling pathways, and the consequences for age-related alterations in the cytoarchitecture and function of the nervous system, will therefore be given considerable attention in this chapter. In order to understand how developmental mechanisms may contribute to normal aging and age-related dysfunction and diseases in the nervous system, it is first necessary to understand the cellular and molecular changes that occur during aging.