Valter Longo - US grants

DESCRIPTON (Provided by applicant): The candidate was trained as a biochemist at UCLA where he specialized in studies of oxidative damage in yeast. Dr. Longo has spent the past three years as a PI of a funded yeast laboratory and as a Research Associate/Assistant Professor working on Alzheimer?s Disease-related projects. The candidate?s long-term career goals are to be a faculty member in a neuroscience program and to continue research on aging. He is applying for the K01 Award in Aging to develop his research skills and knowledge in the neuroscience field with particular focus on the fundamental mechanisms of oxidative damage in aging and neurodegenerative diseases. Dr. Caleb. Finch, Prof. of Gerontology, Neuroscience, and Molecular Biology at the Andrus Gerontology Center, will act as Dr. Longo?s mentor along with Prof. Kelvin Davies. The international stature of these faculty members in the field of aging, oxidative stress, and neurodegenerative diseases, make this environment ideal for the development of Dr. Longo expertise in these fields. Dr Longo will participate in the bimonthly chalk talks in the Neurobiology and Endocrinology of Aging, will attend the weekly research seminars and journal clubs in USC?s multidisciplinary neuroscience program, and will attend a course on the responsible conduct of research. The candidate will also be exposed to clinical studies on cognitive changes during normal aging and during Alzheimer disease (AD). The research project "4 Iron-4 Sulfur Clusters in Aging and Alzheimer?s Disease" proposes to test the hypothesis that the 4Fe-4S clusters, contained in certain dehydratase enzymes sensitive to superoxide toxicity, are a major source of the redox-active iron that mediates oxidative damage during aging and in Alzheimer?s Disease. This hypothesis will be tested by measuring redox-active iron in animal models for AD and by determining the contribution of 4Fe-4S clusters to the pool of redox-active iron and to oxidative damage and death in neurons and neuronal cell lines exposed to oxidants and beta amyloid.

[unreadable] DESCRIPTION (provided by applicant): Mutations in the Sch9 and Ras/cAMP signal transduction pathways, which promote reproduction in response to glucose/nutrients, activate multiple stress resistance systems and extend the life span of non-dividing yeast by up to three-fold. Sch9 is homologous to the C. elegans, Drosophila, and mammalian serine/threonine kinases Akt/PKB, which are also activated in response to glucose/nutrients and function in pathways that regulate reproduction and longevity. I propose that the modulation of analogous signal transduction pathways can increase resistance to damage and extend longevity in organisms ranging from yeast to mammals by shifting the investment of energy from growth and reproduction to multiple stress resistance systems. These mechanisms may have arisen early during evolution in order to minimize aging during periods of starvation. To test this hypothesis I propose to: 1) elucidate the molecular mechanisms responsible for the regulation of longevity by the yeast Ras/cAMP and Sch9 pathways, focusing on known stress resistance genes and on yeast homologs of genes that function in the IGF-1/insulin signaling pathway in higher eukaryotes, 2) perform unbiased screens and study uncharacterized stress resistant mutants isolated in previous screens to identify novel genes that mediate longevity-regulation downstream of Ras/cAMP/Msn2/4 and Sch9, 3) characterize further the post-diauxic life span in wild type and long-lived mutants to understand the relationship between aging in yeast and in higher eukaryotes, 4) identify the distinct mechanisms that regulate the "chronological life span" (survival of non-dividing yeast) and "replicative life span" (budding potential). The combination of the short, high-metabolism post-diauxic life span with transposon mutagenesis provides a rapid method to identify the mediators of stress resistance and longevity extension. The identification and characterization of these mutations should contribute to the identification and understanding of putative dormant starvation-response pathways in mammals, which may be activated to protect cells against aging and age-related diseases without affecting normal functions.

DESCRIPTION (provided by applicant): We propose to bring together laboratories from different disciplines, departments, and universities in Los Angeles to study the molecular mechanisms linking dietary restriction and starvation to cellular protection and aging. These studies will contribute to the identification of drugs and interventions to treat but also prevent multiple diseases of aging. The program project consists of 3 major projects, an Animal and Biostatistics Core and an Administrative Core. The common goals are to: a) identify dietary interventions and molecular pathways that can protect normal cells and organs against both endogenous and exogenous toxins with focus on age-dependent oxidative DNA and protein damage and life span, b) understand the underlying mechanisms of cellular and organismal aging with focus on starvation, growth factors-dependent signaling, oxidative and endoplasmic reticulum (ER) stress, c) test the hypothesis that the modulation of anti aging pathways by starvation, genetic manipulations and drugs can result in differential protection of normal and cancer cells against toxins and extend longevity. The PIs bring together an optimal combination of expertise ranging from those in the genetics and molecular biology of starvation-dependent modulation of aging and stress resistance with focus on IGF-I, IGFBPs, and their signaling pathways, to knowledge of endoplasmic reticulum stress response systems and their link to aging and diseases, to experience with highly challenging procedures and large scale animals studies related to the biology of aging. The unique background of each PI and the close collaborations between them has generated and will continue to generate novel ideas to address the very complex link between growth factors, stress resistance, aging, and diseases. The variety of model systems, genetically modified cells and mice, reagents, and technical expertise contributed by each PI is undoubtedly accelerating the research progress in a way that could not be achieved by independent studies. PUBLIC HEALTH RELEVANCE: Modern research approaches on the major diseases focus primarily on the treatment of these diseases after they are diagnosed. Here, we propose to bring together laljoratories from different disciplines, departments, and universities in the Los Angeles area to understand the molecular mechanisms of cellular protection and aging and apply them to the identifications of drugs and interventions to prevent and treat diseases of aging The unique background of each of the PIs has generated and will continue to generate novel ideas and strategies to address the very complex link between aging and diseases. REVIEW OF INDIVUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE;DR. VALTER, D. LONGO, CORE LEADER (CL) DESCRIPTION (provided by applicant): The overall goal of the administrative core is to provide scientific, fiscal, and organizational coordination of all the activities of the projects and cores, facilitate interactions, regular meetings and technology-sharing and provide oversight and strategic planning for the program as a whole. The aims of Core A are: 1. General Administration including the management of interactions between the projects, communication with the NlA/NIH, fiscal and accounting services and the set up of a website with password for sharing data and manuscripts In preparation. 2. Facilitate Meetings and Sharing, including organizing biweekly meetings of all investigators, meetings with the internal and external advisory committees, and coordinating the sharing of materials, supplies, cells, and animals between the different projects. 3. Progress, including analysis of the data produced by the various components, reading of reports by the Internal and External Advisory Committees, and providing feedback to each Core and Project to ensure that the goals of the program project are maintained. 4. Communication, including exposing university students, researchers and faculty to novel aging research-based strategies to prevent and treat diseases and enhance their interest in biogerontology, working with the administration to organize symposia and public lectures related to biogerontology-based approaches to prevent and treat diseases, setting up a web site to educate the public, researchers and clinicians about the progress of the research performed as part ofthis PO1. PUBLIC HEALTH RELEVANCE: The overall goal of the administrative core is to provide scientific, fiscal, and organizational coordination of all the activities of the projects and cores, facilitate interactions, regular meetings and technology-sharing and provide oversight and strategic planning for the program as a whole.

The insulin like-growth factor (IGF) system is well recognized to control multiple processes including growth, differentiation, cancer and aging. Our preliminary data includes evidence that genetic variations in the GH- IGF system is involved in human longevity and that the IGF-IGFBP system is a potent modulator of cancer progression in vitro and In vivo. In this project, we propose to utilize an array of unique cell lines and mouse models we have established with focus on IGFBP-deficient mice to determine if they exhibit altered life span or altered stress responsiveness and survival in response to oxidative stress and chemotherapy and to see if fasting results in an additive or antagonistic stress response to toxins. We will also investigate the mechanisms responsible for IGFBP-dependent effects on stress resistance and will examine the differential stress response (DSR) effect in murine genetic models of prostate cancer mated into IGF/IGFBP modified strains. Finally, we plan to investigate if IGF modulating drugs mimic or complement the DSR effects of fasting and diet on stress resistance and longevity in these models. The ultimate goal of this project is to test the hypothesis that lGF-1 and IGFBPs play central roles in the modulation of stress resistance as it relates to aging and diseases of aging. This knowledge can be applied to develop pharmacologic and nutritional interventions that will protect older patients against cancer, chemotherapy and radiotherapy, and other age- dependent diseases caused by endogenous toxins. We will therefore pursue the following specific aims: 1) Investigate the mechanism and differential action of IGFBPs on protection and sensitization of normal and transformed cells in vitro. Our hypothesis is that IGFBPs confer a differential stress resistance effect between primary and cancer cell lines through a dual mechanism involving both IGF-inhibition and direct cellular actions. 2) Define the role of IGFBPs in longevity and in vivo stress resistance through the use of the IGFBPS and IGFBPl knockout mice. 3) Examine the effects of IGF-modulating drugs including IGF-1 receptor blocking-antibodies on stress resistance and longevity in mice. 4) Determine the effects of IGF and IGFBPs on survival in prostate cancer models by mating IGF/IGFBP altered mice into genetic prostate cancer models, testing the progression of prostate cancer. Together, these studies will develop new strategies to understand the molecular mechanisms of cellular protection and apply them to differential protection of normal and cancer cells and the development of strategies to enhance healthy aging

DESCRIPTION (provided by applicant): We propose to bring together laboratories from different disciplines, departments, and universities in Los Angeles to study the molecular mechanisms linking dietary restriction and starvation to cellular protection and aging. These studies will contribute to the identification of drugs and interventions to treat but also prevent multiple diseases of aging. The program project consists of 3 major projects, an Animal and Biostatistics Core and an Administrative Core. The common goals are to: a) identify dietary interventions and molecular pathways that can protect normal cells and organs against both endogenous and exogenous toxins with focus on age-dependent oxidative DNA and protein damage and life span, b) understand the underlying mechanisms of cellular and organismal aging with focus on starvation, growth factors-dependent signaling, oxidative and endoplasmic reticulum (ER) stress, c) test the hypothesis that the modulation of anti aging pathways by starvation, genetic manipulations and drugs can result in differential protection of normal and cancer cells against toxins and extend longevity. The PIs bring together an optimal combination of expertise ranging from those in the genetics and molecular biology of starvation-dependent modulation of aging and stress resistance with focus on IGF-I, IGFBPs, and their signaling pathways, to knowledge of endoplasmic reticulum stress response systems and their link to aging and diseases, to experience with highly challenging procedures and large scale animals studies related to the biology of aging. The unique background of each PI and the close collaborations between them has generated and will continue to generate novel ideas to address the very complex link between growth factors, stress resistance, aging, and diseases. The variety of model systems, genetically modified cells and mice, reagents, and technical expertise contributed by each PI is undoubtedly accelerating the research progress in a way that could not be achieved by independent studies.

Overview The overall goal of the administrative core is to provide scientific, fiscal, and organizational coordination of all the activities of the Projects and Cores, facilitate interactions, regular meetings and technology/sample/data- sharing, and provide oversight and strategic planning for the program as a whole. The aims of Core A are: 1. General Administration including the management of the communication and interaction between the projects, communicate with the NIA/NIH program Officers and Directors including the filing of progress reports and publications after acceptance, fiscal and accounting services for all Projects and Cores. This includes travel reimbursements and meeting logistics, maintaining the project website for experiment planning, inventory and data sharing, and manuscript preparation. 2. Facilitate Meetings and Data/Reagent Sharing including organizing bimonthly meetings of all investigators, all meetings to be held at the USC UPC Campus, and organize an annual meeting with the internal advisory board and meetings with the external advisory board every other year, and coordinate the sharing of materials, supplies, cells, and animals between the different projects. 3. Progress Curate the data produced by the various constituents of each Core and Project, and prepare and distribute reports by the Internal and External Advisory Committees, and provide feedback to each Core and Project to ensure that the goals of the program project are met in a timely manner. 4. Communication Work with the USC and Harvard executives to expose university students, researchers and faculty to novel aging research-based strategies to prevent and treat diseases and enhance their interest in biogerontology, and work with the university administration to organize symposia and public lectures related to biogerontology-based approaches to prevent and treat diseases, utilize the project website to inform and educate the public, researchers and clinicians about the progress of the research performed as part of this P01, the parallel clinical studies, and the progress in the area of biogerontology-based approaches in biomedicine.

DESCRIPTION (provided by applicant): Human aging and age-associated diseases are becoming one of the biggest challenges faced by developed and developing countries. The financial burden caused by these chronic diseases is already overwhelming and currently taxing the healthcare and welfare systems of developed nations, but if present trends continue, the challenges could overwhelm the systems. In rodents, both dietary restriction (DR) and mutations in nutrient and growth signaling pathways can extend longevity by 30-50% but also lower the incidence of age-related loss of function and disease, including tumors and neurodegeneration. This application requests funds to support the Consensus Workshop Interventions to Slow Aging in Humans: Are We Ready? to be held in Erice, Sicily, Italy, from October 8-13, 2013. The main aim of the consensus workshop is to bring together leading experts in gerontology, drug discovery and development to begin to obtain consensus related to the discovery and development of safe interventions to slow aging and increase healthspan in humans. The goals of the conference are: 1) To determine the most suitable candidate healthspan interventions/drugs for clinical development, 2) To provide a forum for the discussion of state of the art techniques for drug discovery related to aging and age-related disease, 3) To stimulate clinical trials to begin the testing of drugs generated by basic biogerontology research and discuss the potential pitfalls and side effects of each drug.

? 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.

PROJECT SUMMARY/ABSTRACT TITLE: Dietary Restriction, GH/IGF-1 and Mechanisms of Cellular Protection and Regeneration ABSTACT: 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 leading to 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, fasting mimicking diets and protein restriction to reduced nutrient 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 application consists of 3 major projects, an Animal and Biostatistics Core, and an Administrative Core. Our common goals are to: 1) identify and study novel periodic dietary interventions that promote healthspan without causing adverse effects at old ages; 2) study the mechanisms of fasting mimicking diet- 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, fasting mimicking diets 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 collaboration between them has generated and will continue to generate new hypotheses, novel cellular and mouse models, as well as 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 research independently.