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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG034906-03
Application #
8429461
Study Section
Special Emphasis Panel (ZAG1-ZIJ-5 (05))
Program Officer
Finkelstein, David B
Project Start
2011-03-15
Project End
2016-02-29
Budget Start
2013-06-01
Budget End
2014-02-28
Support Year
3
Fiscal Year
2013
Total Cost
$1,590,315
Indirect Cost
$477,463
Name
University of Southern California
Department
Type
Other Domestic Higher Education
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
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Kim, Su-Jeong; Mehta, Hemal H; Wan, Junxiang et al. (2018) Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY) 10:1239-1256
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Qin, Qing; Delrio, Silvia; Wan, Junxiang et al. (2018) Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction. Int J Cardiol 254:23-27
Guidi, Novella; Longo, Valter D (2018) Periodic fasting starves cisplatin-resistant cancers to death. EMBO J 37:
Buono, Roberta; Longo, Valter D (2018) Starvation, Stress Resistance, and Cancer. Trends Endocrinol Metab 29:271-280
Qin, Qing; Mehta, Hemal; Yen, Kelvin et al. (2018) Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice. Am J Physiol Heart Circ Physiol 315:H1127-H1136
Lee, Amy S; Brandhorst, Sebastian; Rangel, Daisy F et al. (2017) Effects of Prolonged GRP78 Haploinsufficiency on Organ Homeostasis, Behavior, Cancer and Chemotoxic Resistance in Aged Mice. Sci Rep 7:40919
Ben-Avraham, Danny; Govindaraju, Diddahally R; Budagov, Temuri et al. (2017) The GH receptor exon 3 deletion is a marker of male-specific exceptional longevity associated with increased GH sensitivity and taller stature. Sci Adv 3:e1602025

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