The mechanisms responsible for the age dependence of the onset of neurodegeneration are unknown, which represents a fundamental problem both in neuroscience and biogerontology. Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by dementia, deposition of beta amyloid (A?) plaques, and neurofibrillary tau tangles. Despite progress in developing treatments for the symptomatic relief of AD, most drugs only exhibit marginal benefits and no cure currently exists. Epidemiological and preclinical studies provide strong evidence that metabolic derangements including obesity, metabolic syndrome and type 2 diabetes constitute major risk factors for age-related diseases including dementia and AD but the mechanisms involved remain to be elucidated. The GH signaling functions as a central regulator of metabolism and energy use, and it coordinates the physiological responses of the entire organism through hormonal signaling. Mutant animals with reduced GH signaling are not only long-lived, but are protected against age-associated decline in memory and learning. Methionine restriction has been shown previously to extend lifespan and delay aging in both rats and mice, dramatically decrease body weight and adiposity, and improve insulin sensitivity and ameliorate aging-associated alterations in glucose and lipid homeostasis. Thus, combing delaying aging models with AD disease models exhibiting various phenotypic effects provides a novel opportunity to develop new models that will allow studies focused on the interaction between aging, metabolism, and neurodegeneration. Our proposed study will determine if suppression of the GH signaling and methionine restriction will prevent development of behavioral, electrophysiological and histopathologic abnormalities of AD phenotype can serve as a model to study the interaction of aging with AD, providing a new level of analysis of the human brain in health and disease.
The proposed research is aim to address a crucial public health issue in a cost-effective manner because the aging of the Baby Boomer generation is resulting in a massive increase in the absolute number and proportion of elderly Americans. Age is the biggest risk factor for many diseases, leading to increased cost of healthcare. This project will develop new models to study hormonal signaling, cognitive aging and neurodegenerative diseases in the context of mutations that slow the aging process, and serve as a foundation for promising novel approach for the development of counter-neurodegenerative therapy.
