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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
2P01AG025532-06A1
Application #
8415623
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2 (02))
Program Officer
Finkelstein, David B
Project Start
2004-12-01
Project End
2017-11-30
Budget Start
2012-12-15
Budget End
2013-11-30
Support Year
6
Fiscal Year
2013
Total Cost
$1,060,953
Indirect Cost
$310,519
Name
University of California Davis
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
McMackin, Marissa Z; Henderson, Chelsea K; Cortopassi, Gino A (2017) Neurobehavioral deficits in the KIKO mouse model of Friedreich's ataxia. Behav Brain Res 316:183-188
Granatiero, Veronica; Gherardi, Gaia; Vianello, Matteo et al. (2017) Role of p66shc in skeletal muscle function. Sci Rep 7:6283
Song, Lanying; Yu, Alfred; Murray, Karl et al. (2017) Bipolar cell reduction precedes retinal ganglion neuron loss in a complex 1 knockout mouse model. Brain Res 1657:232-244
Taylor, Sandra L; Ruhaak, L Renee; Weiss, Robert H et al. (2017) Multivariate two-part statistics for analysis of correlated mass spectrometry data from multiple biological specimens. Bioinformatics 33:17-25
Roberts, Megan N; Wallace, Marita A; Tomilov, Alexey A et al. (2017) A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab 26:539-546.e5
Baldassini, W A; Ramsey, J J; Hagopian, K et al. (2017) The influence of Shc proteins and high-fat diet on energy metabolism of mice. Cell Biochem Funct 35:527-537
Taylor, Sandra L; Ruhaak, L Renee; Kelly, Karen et al. (2017) Effects of imputation on correlation: implications for analysis of mass spectrometry data from multiple biological matrices. Brief Bioinform 18:312-320
Datta, Sandipan; Baudouin, Christophe; Brignole-Baudouin, Francoise et al. (2017) The Eye Drop Preservative Benzalkonium Chloride Potently Induces Mitochondrial Dysfunction and Preferentially Affects LHON Mutant Cells. Invest Ophthalmol Vis Sci 58:2406-2412
Hagopian, Kevork; Kim, Kyoungmi; López-Dominguez, José Alberto et al. (2016) Mice with low levels of Shc proteins display reduced glycolytic and increased gluconeogenic activities in liver. Biochem Biophys Rep 7:273-286
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

Showing the most recent 10 out of 95 publications