PROJECT SUMMARY (Neuronal microtubule regulation and its autonomous and non-autonomous effects on aging) Aging is the greatest risk factor for developing neurodegenerative diseases including Alzheimer's Disease (AD). Neuronal aging, defined as a progressive loss of function and structure, predisposes neurons to degeneration. The importance of microtubule (MT) regulation in neurons is underscored by the critical role of MT-associated proteins, e.g. tau and tau-like proteins, whose dysfunction leads to neurodegeneration. Surprisingly, little is known about the role of MTs in the normal aging process. MT regulation is involved on several levels of neuronal function and maintenance of structure, and MT regulation also appears to be a general downstream indicator and effector in age-dependent neurodegeneration. The cause and effect relationship between MT defects and cellular dysfunction is not clear. In C. elegans, it has been demonstrated that mutations in protein with tau-like repeats (ptl-1), an ortholog of tau/MAP2/MAP4, leads to defective neuronal function and an accelerated occurrence of age-associated morphological changes. On the other hand, it has also been shown that mutations in other MT regulators delay the onset of age-related changes. These data show defects in MTs are not only associated with, but also contribute to, neuronal aging. The goals of this proposed study are to define changes in MT status associated with neuronal aging and to characterize mechanisms by which MT defects affect neuronal function. Preliminary data indicate mutations in multiple MT regulators are sufficient to influence lipid metabolism and lifespan. The central hypothesis is preservation of MT polymerization in neurons delays neuronal aging and promotes longevity through gap junctions. In Aim 1, we will test whether loss of MT polymerization causes neuronal aging. In Aim 2, we will test whether neuronal MT perturbation regulates longevity and peripheral lipid metabolism via gap junctional signaling. Confocal imaging, molecular, biochemical and C. elegans genetic approaches will be used to fulfil these aims. Data generated from this proposal will not only increase our understanding of the roles played by MT regulation in the neuronal and organismal aging, but also potentially lead to novel targets to delay aging and its associated diseases.