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Dietary Restriction, GH/IGF-l & Mechanisms of Cellular Protection and Regeneration

饮食限制，GH/IGF-l

基本信息

批准号：
9074571
负责人：
VALTER D. LONGO
金额：
$ 107.3万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-15 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9074571
关键词：
Address Adverse effects Age Aging Aging-Related Process Animals Area Atrophic Biological Assay Biological Models Biology of Aging Biostatistics Core California Caloric Restriction Calories Cardiovascular Diseases Cell model Cells Cellular biology Chronic Clinical Trials Collaborations Complex Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cysteine Development Diet Dietary Intervention Disease Essential Amino Acids Fasting Foundations Funding Generations Genes Genetic Gerontology Glucose Goals Growth Health Hematopoietic System Human Hydrogen Sulfide Immune system Incidence Injury Insulin-Like Growth Factor I Intervention Investigation Ketone Bodies Laboratories Link Lyase Malignant Neoplasms Mediating Mediator of activation protein Metabolic Minor Mitochondria Molecular Molecular Biology Morbidity - disease rate Mus Natural regeneration Nervous system structure Neurodegenerative Disorders Organ Oxidative Stress Pathway interactions Peptides Pharmaceutical Preparations Positioning Attribute Production Proteins Reagent Regulation Rejuvenation Research Resistance Respiration Risk Factors Schools Signal Pathway Signal Transduction Stem cells Stress System Technical Expertise Testing Translating Universities analog base body system cell type dietary restriction experience feeding genetically modified cells human subject humanin improved mimetics mouse model new therapeutic target novel nutrition pre-clinical prevent programs protective effect public health relevance sugar transcription factor

项目摘要

DESCRIPTION (provided by applicant): Age is the major risk factor for many morbidities including cancer, cardiovascular and neurodegenerative diseases. Biogerontology research is well positioned to help prevent or at least delay these diseases by identifying safe strategies to retard aging so that the degree and type of cellular damage does not reach the threshold required for disease incidence or progression. Here we propose to bring together two biogerontology laboratories from the University of Southern California School of Gerontology and a laboratory from Harvard University to study the molecular mechanisms linking fasting and protein restriction to reduced growth factor signaling, the stress resistance signaling network, the mitochondrial peptide humanin, and in turn, cellular protection, regeneration, and healthspan. These studies will contribute to the identification of drugs and dietary interventions to treat as well as prevent multiple diseases by acting on the aging process and on multi-system regeneration and rejuvenation. An important advantage of the dietary interventions being tested is that they are periodic and therefore have the potential to match and possibly surpass the beneficial effects of chronic calorie restriction while minimizing the burden of chronic and extreme diets, but also minimizing adverse effects. This P01 renewal application consists of 3 major projects, an Animal and Biostatistics Core, and an Administrative Core. Our common goals are to: 1) study previously established and identify novel periodic dietary interventions tha promote healthspan without causing adverse effects at old ages; 2) study the mechanisms of fasting and protein restriction-dependent cellular protection, regeneration and rejuvenation with focus on the hematopoietic and nervous systems; 3) understand the link between dietary interventions, growth pathways and humanin to test the hypothesis that this mitochondrial peptide functions as a healthspan mediator and determine whether it can serve as a fasting/protein restriction mimetic; 4) test the hypothesis that endogenous H2S is a key mediator of the protective effects of dietary interventions including fasting and protein restriction on resistance to ischemic and genotoxic injury to organs and cells, and study the regulation of cysteine gamma lyase-mediated endogenous H2S production by dietary restriction, growth factors and humanin. The unique background of each PI and the close collaborations between them has generated and will continue to generate new hypotheses, a variety of novel cellular and mouse models, assays, and technical and conceptual developments. These advances, will undoubtedly accelerate the research progress, and support the development of clinical trials to improve human health in ways that could not be achieved by each laboratory performing this research independently.

描述（由申请人提供）：年龄是许多疾病的主要风险因素，包括癌症、心血管和神经退行性疾病。生物老年学研究是很好的定位，以帮助预防或至少延迟这些疾病，通过确定安全的策略，以延缓衰老，使细胞损伤的程度和类型不会达到疾病的发病率或进展所需的阈值。在这里，我们建议将南加州大学老年学学院的两个老年学实验室和哈佛大学的一个实验室聚集在一起，研究禁食和蛋白质限制与生长因子信号传导减少、抗应激信号传导网络、线粒体肽humanin以及细胞保护、再生和健康寿命之间的分子机制。这些研究将有助于确定药物和饮食干预措施，通过作用于衰老过程和多系统再生和恢复活力来治疗和预防多种疾病。正在测试的饮食干预措施的一个重要优点是，它们是周期性的，因此有可能达到并可能超过长期热量限制的有益效果，同时最大限度地减少长期和极端饮食的负担，但也最大限度地减少不利影响。该P01更新申请包括3个主要项目，动物和生物统计学核心以及行政核心。我们的共同目标是：1）研究先前建立的并确定新的周期性饮食干预措施，以促进健康，而不会对老年人造成不良影响; 2）研究禁食和蛋白质限制依赖的细胞保护，再生和复兴的机制，重点是造血和神经系统; 3）了解饮食干预之间的联系，生长途径和humanin，以测试这种线粒体肽作为健康维持介质的假设，并确定它是否可以作为禁食/蛋白质限制模拟物; 4）验证内源性H2S是禁食和限制蛋白质摄入等饮食干预措施对器官和细胞抗缺血性和遗传毒性损伤的保护作用的关键介质的假设，并研究饮食限制、生长因子和humanin对半胱氨酸γ裂解酶介导的内源性H2S产生的调节作用。每个PI的独特背景和他们之间的密切合作已经产生并将继续产生新的假设，各种新的细胞和小鼠模型，测定以及技术和概念发展。这些进展无疑将加速研究进展，并支持临床试验的发展，以改善人类健康，而这是每个实验室独立进行这项研究所无法实现的。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Targeting Cancer Metabolism: Dietary and Pharmacologic Interventions.

DOI：
10.1158/2159-8290.cd-16-0615
发表时间：
2016-12
期刊：
Cancer discovery
影响因子：
28.2
作者：
Vernieri C;Casola S;Foiani M;Pietrantonio F;de Braud F;Longo V
通讯作者：
Longo V

A radical signal activates the epigenetic regulation of longevity.

DOI：
10.1016/j.cmet.2013.05.015
发表时间：
2013-06
期刊：
Cell metabolism
影响因子：
29
作者：
M. Mirisola;V. Longo
通讯作者：
M. Mirisola;V. Longo

Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer.

DOI：
10.1038/srep19569
发表时间：
2016-01-22
期刊：
Scientific reports
影响因子：
4.6
作者：
Marini C;Bianchi G;Buschiazzo A;Ravera S;Martella R;Bottoni G;Petretto A;Emionite L;Monteverde E;Capitanio S;Inglese E;Fabbi M;Bongioanni F;Garaboldi L;Bruzzi P;Orengo AM;Raffaghello L;Sambuceti G
通讯作者：
Sambuceti G

The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like Peptide 2, Exhibit Chaperone-like Activity.