Liou Y. Sun - US grants

? DESCRIPTION (provided by applicant): Caloric restriction (CR) is the well-studied dietary intervention to prolong longevity and retard aging in a wide range of species. Methionine restriction (MR) has also been shown to extend lifespan in rodents. In addition, we have shown that MR diet could increase mouse lifespan even if initiated at middle age. In contrast with the CR, the mechanisms how MR diets extend longevity and delay aging have been less explored. Despite some similarities between CR and MR effects, distinct features including increased food consumption in MR animals, different gene expression patterns and disparities in activation of cellular signaling pathways have been documented. These evidences have strongly supported the idea that MR diets might slow aging through routes that do not mimic those of CR. Our long-term objective is to identify the molecular mechanisms responsible for the increase in lifespan and health span of animals exposed to MR. Our grant proposal is designed to test the hypothesis that MR diet slows aging through increasing metabolic flexibility and insulin sensitivity, enhancing stress resistance signaling and modulating the somatotropic axis in mice. The research proposed will test a series of hypotheses about the mechanism of lifespan extension in MR mice. A comprehensive analysis a broad range of end points, from the assessment of molecular changes, functional parameters, metabolic homeostasis, stress pathways to very basic physiological alterations should have a high impact on the field of aging since the fundamental mechanisms underlying the beneficial effects of MR remain largely unknown. The outcomes of this proposal will provide the important mechanistic advances to our current understanding of the differential mechanisms of action of two of the most powerful models for lifespan extension in mammals.

The greatest risk factor for nearly all the neurodegenerative diseases is aging. The mechanisms for the age- dependent onset of neurodegeneration are unknown, which represents a fundamental problem both in the field. Studies in a variety of model organisms from yeast to rodents identify pathways that modulate aging. In mice, reduced somatotropic axis activity (or GHRH-GH-IGF1 pathway) leads to major increases in lifespan and healthspan. Murine mutant mice with slow rates of aging and murine AD disease models with varying phenotypic effects provide the opportunity to develop novel genetic models that will allow to study the interaction of aging and neurodegeneration. The long-term goal of our research is to understand the molecular basis of brain aging and the way in which aging contributes to pathological aging and neurodegenerative disorders. Our objective is to elucidate the role of the somatotropic axis in the age-dependent susceptibility to AD. Our hypothesis is that slowing aging by inhibiting the somatotropic axis will delay mortality and retard the development of behavioral and pathologic abnormalities secondary to A? toxicity in mice. This proposal, if successful, should lead to new models to study the interaction of aging with neurodegenerative diseases in the context of mutations that slow the aging process, and serve as a foundation for future work toward the development of interventions to prevent, retard, or treat neurodegenerative diseases. Our models would be also used to pursue mechanistic hypotheses about age-related processes that modulate AD and other late-life neurodegenerations.

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 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.