Obesity and diabetes are epidemic in the U.S. The consequences and comorbidities of obesity and diabetes have a massive negative impact on the aged, and thus strategies to combat obesity and diabetes could have a major impact on a major problem for the aging U.S. population. Twenty years of basic genetic research into aging and longevity across multiple species has also implicated insulin control, via the insulin/igf-1 pathway, and reduced adiposity as critical features of healthy aging. Thus, public health studies and basic aging studies converge and suggest that mechanisms to combat obesity and diabetes could have a major impact on the health of seniors. In the previous award, the program project assembled an experienced team to understand and integrate the consequences of Shc-deficiency at the molecular, organellar, tissue and whole-organismal levels. The research conducted demonstrated that Shc knockout (KO) mice resist obesity and diabetes, through increased insulin/igf-1 signaling and a 'low-insulin lifestyle,'are stress resistant, and have majr modifications of metabolism, extended median lifespan on caloric restriction, and increased stem cell function. In the current proposal, the program project will identify the Shc-based mechanism of: 1) decreased adiposity and increased survival on high-fat diet in mutant mice, 2) extended median lifespan on caloric restriction, and 3) improved stem cell function. In addition, the program will 4) identify drugs and diets that simulate Shc-deficiency, to be used as leads to promote healthy human aging. Thus, the ultimate product of the work will be not only a detailed understanding of the anti-obesity mechanism, anti-diabetic and anti-stress functions of Shcs, but also lead compounds and nutritional interventions that support healthy aging.

Public Health Relevance

Obesity and diabetes and their comorbid complications have a massive impact on our aging seniors, and the high-fat Western diet contributes. We seek to identify the mechanisms by which ShcKO mice resist obesity and diabetes and stress, and to identify nutritional and pharmacological inducers of healthy aging exhibited by these mice.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-2 (02))
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Finkelstein, David B
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University of California Davis
Veterinary Sciences
Schools of Veterinary Medicine
United States
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Tosatto, Anna; Sommaggio, Roberta; Kummerow, Carsten et al. (2016) The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1α. EMBO Mol Med 8:569-85
Datta, Sandipan; Sahdeo, Sunil; Gray, Jennifer A et al. (2016) A high-throughput screen for mitochondrial function reveals known and novel mitochondrial toxicants in a library of environmental agents. Mitochondrion 31:79-83
Taylor, Sandra L; Ruhaak, L Renee; Kelly, Karen et al. (2016) Effects of imputation on correlation: implications for analysis of mass spectrometry data from multiple biological matrices. Brief Bioinform :
Tian, Jijing; Yang, Guoxiang; Chen, Huan-Yuan et al. (2016) Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 30:4202-4213
Raffaello, Anna; Mammucari, Cristina; Gherardi, Gaia et al. (2016) Calcium at the Center of Cell Signaling: Interplay between Endoplasmic Reticulum, Mitochondria, and Lysosomes. Trends Biochem Sci 41:1035-1049
Tomilov, Alexey; Tomilova, Natalia; Shan, Yuxi et al. (2016) p46Shc Inhibits Thiolase and Lipid Oxidation in Mitochondria. J Biol Chem 291:12575-85
Datta, Sandipan; Tomilov, Alexey; Cortopassi, Gino (2016) Identification of small molecules that improve ATP synthesis defects conferred by Leber's hereditary optic neuropathy mutations. Mitochondrion 30:177-86
Shen, Yan; McMackin, Marissa Z; Shan, Yuxi et al. (2016) Frataxin Deficiency Promotes Excess Microglial DNA Damage and Inflammation that Is Rescued by PJ34. PLoS One 11:e0151026
Taylor, Sandra L; Ruhaak, L Renee; Weiss, Robert H et al. (2016) Multivariate two-part statistics for analysis of correlated mass spectrometry data from multiple biological specimens. Bioinformatics :
Song, Lanying; Cortopassi, Gino (2015) Mitochondrial complex I defects increase ubiquitin in substantia nigra. Brain Res 1594:82-91

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