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.
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.
|Roberts, Megan N; Wallace, Marita A; Tomilov, Alexey A et al. (2018) A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab 27:1156|
|Penna, Elisa; Espino, Javier; De Stefani, Diego et al. (2018) The MCU complex in cell death. Cell Calcium 69:73-80|
|Pallafacchina, Giorgia; Zanin, Sofia; Rizzuto, Rosario (2018) Recent advances in the molecular mechanism of mitochondrial calcium uptake. F1000Res 7:|
|Jasoliya, Mittal J; McMackin, Marissa Z; Henderson, Chelsea K et al. (2017) Frataxin deficiency impairs mitochondrial biogenesis in cells, mice and humans. Hum Mol Genet 26:2627-2633|
|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|
|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|
|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|
|Hayashi, Genki; Jasoliya, Mittal; Sahdeo, Sunil et al. (2017) Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Hum Mol Genet 26:2864-2873|
|Wright, Lauren E; Vecellio Reane, Denis; Milan, Gabriella et al. (2017) Increased mitochondrial calcium uniporter in adipocytes underlies mitochondrial alterations associated with insulin resistance. Am J Physiol Endocrinol Metab 313:E641-E650|
|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|
Showing the most recent 10 out of 103 publications