11 Indeed, presenilin-1 was also reported to have roles in autophagy-mediated protein degradation.12,13 In addition, AD is characterized by the formation of intra-cellular tangles of hyper-phosphorylated TAU, a microtubule-associated protein. The links of these tangles to the etiology of AD are largely obscure.6 Parkinson’s disease (PD) is a common movement disorder that

emerges as a result of aberrant aggregation of the protein α-synuclein. This aggregation process Inhibitors,research,lifescience,medical decimates the dopaminergic neurons of the substantia nigra, resulting in various phenotypes including tremor, rigidity, and impaired movement.14 Similarly, the aggregation of mutant huntingtin, bearing an abnormally long polyglutamine stretch (polyQ), causes Huntington disease (HD).15 Most cases of AD and PD manifest sporadically during the seventh decade of life or later, while the rarer familial, mutation-linked cases appear during the patient’s fifth or sixth decade of life. The common temporal emergence pattern of different neurodegenerative

Inhibitors,research,lifescience,medical maladies defines aging as the major risk factor for the development of these disorders.16 One possible explanation for the observation that diseases which exhibit different etiologies and cell biological features onset in surprisingly similar temporal emergence patterns suggests that the aging process plays an active role in enabling Inhibitors,research,lifescience,medical neurodegenerative maladies to onset late in life. This model suggests that protective mechanisms that prevent neurodegenerative disorders from emerging early in life are negatively regulated by aging, a process that exposes the aged organism to proteotoxicity and disease. The exploration of aging-regulating Inhibitors,research,lifescience,medical pathways during the last two decades enabled a comprehensive evaluation of this hypothesis. AGING IS A HIGHLY REGULATED PROCESS Three independent mechanisms have been found to regulate

aging and lifespan of model organisms: dietary restriction,17,18 Inhibitors,research,lifescience,medical the mitochondrial electron transport chain,19–21 and the insulin/IGF signaling (IIS) pathway.22,23 Among these, the IIS is the most prominent and best why characterized mechanism whose knock-down possesses the most prominent effect on lifespan of flies, worms, and mice.22 In the nematode GSK1363089 concentration Caenorhabditis elegans (C. elegans) DAF-2, the sole insulin/IGF receptor, initiates a signaling cascade that negatively regulates its downstream transcription factors, DAF-16/FOXO, SKN-1/NRF, and the heat-shock factor 1 (HSF-1). The IIS activates a set of kinases that directly phosphorylate DAF-1624 and SKN-125 to prevent their entry to the nucleus. Similarly, the IIS negatively regulates HSF-1 by preventing the phosphorylation of DDL-1, an HSF-1-interacting protein that when not phosphorylated retains this transcription factor in the cytosol.