The identification of the genes and pathways that regulate the life span in simple model organisms has been invaluable to the initial understanding of the mechanisms of aging in mammals. The systems biology and genetic studies proposed in this application will help define the role of various signal transduction genes and pathways in the regulation of aging and resistance to the damage caused by various stresses in the unicellular eukaryote S. cerevisiae. These pathways are centered around the Ras and Sch9 proteins, which are conserved from yeast to humans, and are implicated in cancer and other diseases. The proposed studies will: 1) shed light on the fundamental molecular mechanisms responsible for the effects of previously identified pro-aging genes including RAS2 and SCH9, 2) investigate novel molecules, genes, and pathways that affect aging and resistance to damage and that may be conserved from yeast to humans, 3) develop a novel paradigm to study aging, that is simpler and more directly relevant to aging in mammals, 4) investigate the anti-aging molecular mechanisms of calorie restriction which appear to be conserved from yeast to mammals. The proposed studies will contribute to the description of the fundamental mechanisms of aging and also to the identification of novel genes and pathways that can protect against human diseases. Public Health Relevance: Historically, simple model systems including baker's yeast, nematodes, and flies have yielded a remarkable number of discoveries that have provided the foundation for the understanding and treatment of human diseases. The studies proposed in this application are aimed at understanding how yeast genes that are analogous to the human genes Ras and Akt affect aging and the protection of cells against damage. The understanding of how these genes regulate aging in yeast and other simple systems will accelerate the identification of genes and pathways that can be modulated to protect against diseases in humans (Longo and Finch, 2003). For example, mutations that cause activation of Akt or Ras accelerate aging in yeast but are also found in a major portion of human cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG020642-10
Application #
8220819
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Guo, Max
Project Start
2002-04-01
Project End
2013-05-31
Budget Start
2012-01-01
Budget End
2013-05-31
Support Year
10
Fiscal Year
2012
Total Cost
$316,023
Indirect Cost
$120,947
Name
University of Southern California
Department
None
Type
Other Domestic Higher Education
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Longo, Valter D; Panda, Satchidananda (2016) Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell Metab 23:1048-59
Mirzaei, Hamed; Raynes, Rachel; Longo, Valter D (2016) The conserved role of protein restriction in aging and disease. Curr Opin Clin Nutr Metab Care 19:74-9
Choi, In Young; Piccio, Laura; Childress, Patra et al. (2016) A Diet Mimicking Fasting Promotes Regeneration and Reduces Autoimmunity and Multiple Sclerosis Symptoms. Cell Rep 15:2136-46
Longo, Valter D; Antebi, Adam; Bartke, Andrzej et al. (2015) Interventions to Slow Aging in Humans: Are We Ready? Aging Cell 14:497-510
Shim, Hong Seok; Wei, Min; Brandhorst, Sebastian et al. (2015) Starvation promotes REV1 SUMOylation and p53-dependent sensitization of melanoma and breast cancer cells. Cancer Res 75:1056-67
Brandhorst, Sebastian; Choi, In Young; Wei, Min et al. (2015) A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab 22:86-99
Block, Keith I; Gyllenhaal, Charlotte; Lowe, Leroy et al. (2015) Designing a broad-spectrum integrative approach for cancer prevention and treatment. Semin Cancer Biol 35 Suppl:S276-304
Mirzaei, Hamed; Longo, Valter D (2014) Acetyl-CoA synthetase is a conserved regulator of autophagy and life span. Cell Metab 19:555-7
Hu, Jia; Wei, Min; Mirzaei, Hamed et al. (2014) Tor-Sch9 deficiency activates catabolism of the ketone body-like acetic acid to promote trehalose accumulation and longevity. Aging Cell 13:457-67
Levine, Morgan E; Suarez, Jorge A; Brandhorst, Sebastian et al. (2014) Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab 19:407-17

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