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
Granatiero, Veronica; Patron, Maria; Tosatto, Anna et al. (2014) Using targeted variants of aequorin to measure Ca2+ levels in intracellular organelles. Cold Spring Harb Protoc 2014:86-93
Chen, Y; Hagopian, K; Bibus, D et al. (2014) The influence of dietary lipid composition on skeletal muscle mitochondria from mice following eight months of calorie restriction. Physiol Res 63:57-71
Tomilov, Alexey; Bettaieb, Ahmed; Kim, Kyoungmi et al. (2014) Shc depletion stimulates brown fat activity in vivo and in vitro. Aging Cell 13:1049-58
Patron, Maria; Checchetto, Vanessa; Raffaello, Anna et al. (2014) MICU1 and MICU2 finely tune the mitochondrial Ca2+ uniporter by exerting opposite effects on MCU activity. Mol Cell 53:726-37
Sahdeo, Sunil; Tomilov, Alexey; Komachi, Kelly et al. (2014) High-throughput screening of FDA-approved drugs using oxygen biosensor plates reveals secondary mitofunctional effects. Mitochondrion 17:116-25
Logan, Clare V; Szabadkai, Gyorgy; Sharpe, Jenny A et al. (2014) Loss-of-function mutations in MICU1 cause a brain and muscle disorder linked to primary alterations in mitochondrial calcium signaling. Nat Genet 46:188-93
Granatiero, Veronica; Patron, Maria; Tosatto, Anna et al. (2014) The use of aequorin and its variants for Ca2+ measurements. Cold Spring Harb Protoc 2014:9-16
Stern, Jennifer H; Kim, Kyoungmi; Ramsey, Jon J (2014) The influence of shc proteins on the whole body energetic response to calorie restriction initiated in 3-month-old mice. ISRN Nutr 2014:562075
Bock, Fabian; Shahzad, Khurrum; Wang, Hongjie et al. (2013) Activated protein C ameliorates diabetic nephropathy by epigenetically inhibiting the redox enzyme p66Shc. Proc Natl Acad Sci U S A 110:648-53
Chen, Yana; Hagopian, Kevork; Bibus, Douglas et al. (2013) The influence of dietary lipid composition on liver mitochondria from mice following 1 month of calorie restriction. Biosci Rep 33:83-95

Showing the most recent 10 out of 58 publications