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.

Public Health Relevance

OVERALL NARRATIVE We propose to bring together two biogerontology laboratories from the University of Southern California and a laboratory from Harvard University to study the molecular mechanisms linking fasting, fasting mimicking diets and protein restriction to growth genes, the stress resistance signaling network, mitochondrial biology, cellular protection, regeneration, and aging. These studies will contribute to the identification of drugs and interventions to treat and prevent multiple diseases by acting on the aging process and on multi-system regeneration and rejuvenation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
3P01AG055369-01A1S2
Application #
9699851
Study Section
Program Officer
Fridell, Yih-Woei
Project Start
2018-02-15
Project End
2023-01-31
Budget Start
2018-09-07
Budget End
2019-01-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Southern California
Department
Type
Other Specialized Schools
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Yen, Kelvin; Wan, Junxiang; Mehta, Hemal H et al. (2018) Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans. Sci Rep 8:14212
Henning, Susanne M; Galet, Colette; Gollapudi, Kiran et al. (2018) Phase II prospective randomized trial of weight loss prior to radical prostatectomy. Prostate Cancer Prostatic Dis 21:212-220
Mao, Kai; Quipildor, Gabriela Farias; Tabrizian, Tahmineh et al. (2018) Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice. Nat Commun 9:2394
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
Xiao, Jialin; Cohen, Pinchas; Stern, Mariana Carla et al. (2018) Mitochondrial biology and prostate cancer ethnic disparity. Carcinogenesis 39:1311-1319
Nencioni, Alessio; Caffa, Irene; Cortellino, Salvatore et al. (2018) Fasting and cancer: molecular mechanisms and clinical application. Nat Rev Cancer 18:707-719
Nashine, Sonali; Cohen, Pinchas; Nesburn, Anthony B et al. (2018) Characterizing the protective effects of SHLP2, a mitochondrial-derived peptide, in macular degeneration. Sci Rep 8:15175
Guidi, Novella; Longo, Valter D (2018) Periodic fasting starves cisplatin-resistant cancers to death. EMBO J 37:
Liang, Pei; Henning, Susanne M; Guan, Johnny et al. (2018) Role of Host GPR120 in Mediating Dietary Omega-3 Fatty Acid Inhibition of Prostate Cancer. J Natl Cancer Inst :
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