Age-related disease is arguably the single greatest challenge for biomedicine in the 21st Century.Age is the largest single risk factor for a panoply of diseases, including cardiovascular dysfunction, cancer,type II diabetes, osteoporosis, and neurodegeneration. Postponing (or decreasing the rate of) aging wouldretard the course of multiple age-related diseases and therefore substantially increase average health-span.Our ability to develop rational approaches to preventing or intervening in aging depends crucially on athorough understanding of the basic mechanisms that cause aging, as well as the etiology of specific agerelateddiseases. We believe that it is especially in this area of biomedicine where an interdisciplinaryapproach will accelerate discoveries and provide rational avenues for therapeutic intervention. In the longterm this will lead to the establishment of a comprehensive new discipline, that of 'Geroscience.' Despitehaving identified 100s of genes that determine lifespan in simple organisms, we have no true understandingof how these genes are impacting on aging and disease. This is in part that most studies are carried inisolation by either looking at the basic biology of aging or separately at the impact of these identified geneson disease. In this proposal, which is directly relevant to Specfic Aim 1 of the U54, Specific Aim 1. Toestablish an interdisciplinary research program on the aging-disease relationship with a focus onneurodegeneration and cancer, we will address across three neurodegenerative disease models,Huntington's disease-Dr. Ellerby (Component 7), Dr. Hughes (Component 6), Dr. Nicholls and Gibson(Component 11), Parkinson's disease-Dr. Andersen (Component 9) and Alzheimer's disease-Dr.Bredesen (Component 1), and the model organism C. elegans-Dr. Kapahi (Component 2)- the role ofhistone deacetylase (HDACs) in neurodegeneration and aging. This represents a significant area asresearchers have made a series of important discoveries in recent years on neurodegenerative disease andin aging that these enzymes (HDACs) play a major in role in neurodegeneration or aging. However,researchers have not yet dissected out in mammalian systems which family members are critical to target toprevent neurodegeneration and aging. A central theme of these projects is the notion that genes that areknown to modulate aging are key factors in determining disease. Drugs that target the maintenancefunctions of these regulators or enhance their function will be important targets for proposed interventions.Our hypothesis is that compromised acetylation homoeostasis is directed coupled toneurodegeneration and identification of particular HDACs family members involved in this processwill identify therapeutic targets critical to neurodegeneration and aging.
