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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Cellular Mechanisms in Aging and Development Study Section (CMAD)
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Guo, Max
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University of Southern California
Other Domestic Higher Education
Los Angeles
United States
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Mirzaei, Hamed; Longo, Valter D (2014) Acetyl-CoA synthetase is a conserved regulator of autophagy and life span. Cell Metab 19:555-7
Mirisola, Mario G; Taormina, Giusi; Fabrizio, Paola et al. (2014) Serine- and threonine/valine-dependent activation of PDK and Tor orthologs converge on Sch9 to promote aging. PLoS Genet 10:e1004113
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
Cheng, Chia-Wei; Adams, Gregor B; Perin, Laura et al. (2014) Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell 14:810-23
Longo, Valter D; Mattson, Mark P (2014) Fasting: molecular mechanisms and clinical applications. Cell Metab 19:181-92
Mirzaei, Hamed; Suarez, Jorge A; Longo, Valter D (2014) Protein and amino acid restriction, aging and disease: from yeast to humans. Trends Endocrinol Metab 25:558-66
Brandhorst, Sebastian; Wei, Min; Hwang, Saewon et al. (2013) Short-term calorie and protein restriction provide partial protection from chemotoxicity but do not delay glioma progression. Exp Gerontol 48:1120-8
Bartke, Andrzej; Sun, Liou Y; Longo, Valter (2013) Somatotropic signaling: trade-offs between growth, reproductive development, and longevity. Physiol Rev 93:571-98
Lee, Changhan; Raffaghello, Lizzia; Brandhorst, Sebastian et al. (2012) Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 4:124ra27

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