She knockout (KO) mice have multiple features of healthy aging, including reduced adiposity, resistance to high-fat diets, stress resistance, and increased stem cell renewal capacity. She mice have increased median longevity on a calorie-restricted diet, and have increased survival on high-fat diets in a pilot study. There are multiple metabolic similarities observed in common among ShcKO and CR mice: reduced insulin levels, decreased glucose levels, increased insulin sensitivity, decreased oxidation of carbohydrates, and increased oxidation of lipids and proteins. Thus we have multiple goals in Project 2: 1) to identify the mechanism(s) by which ShcKO mice resist adiposity and stress, 2) to understand the mechanism by which She depletion extends median lifespan on CR, and 3) to identify She-inhibitory drugs that could be used to improve insulin signaling and healthy aging. Impact and Significance. The research will have substantial impact. First, we as Westerners live in a high fat environment, and| obesity and diabetes and their consequent co morbidities of stroke and cardiovascular disease are a massive health problem for aging Americans. Thus, identifying anti-adiposity mechanisms in She mice could have important implications reducing adiposity and extending health span in humans. Second, longevity-inducing mutations in the insulin/lgf-1 pathway and CR appear to share some similarities of mechanism, and CR inhibits Shcs. Thus we suspect that CR and She mechanisms at least partially overlap, which is supported by the increased median lifespan of ShcKO mice on CR. Third, She mutant mice and their cells are resistant to multiple stressors and appear to have altered autophagy and increased stem cell regeneration, which could have benefit in understanding the mechanisms of age-related stress resistance. Finally, screening has the potential to identify novel She-inhibitory drugs to translate the healthy aging of ShcKO mice to humans. Thus we plan to have an impact on the mechanisms for resistance to adiposity and diabetes, and the identification of small molecules and diets that promote healthy aging in humans.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAG1-ZIJ-2)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
United States
Zip Code
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