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Spindler, Stephen R
Professor Of Biochemistry & Biochemist
Research Specialization - The rate of animal aging is strongly influenced by diet. The more calories consumed, the faster it ages. Well-fed animals not only age faster, they have higher mortality from cancer, heart disease, and diabetes. And the reverse is true, the fewer calories eaten (provided malnutrition is avoided) the slower an animal ages, the lower the death rate from cancer, and the lower the rate of heart disease and diabetes. This dietary regimen of under-nutrition without malnutrition is called calorie restriction. The positive relationship between calorie restriction, health and longevity has been found from mammals to insects to worms. We are very interested in these responses to calorie restriction. Our studies have shown that calorie restriction reduces expression of families of endoplasmic reticulum stress response/molecular chaperones. Reduced chaperone expression increases apoptosis. Increased apoptosis decreases cancer incidence. We have shown that reduced endoplasmic reticulum chaperone levels greatly increases the secretion of serum proteins by the liver. Increased serum protein secretion should cause old proteins to be cleared from the blood faster, reducing the amount of the toxic, glycated proteins in the blood. Glycated proteins cause micro- and macrovascular damage which results in kidney diseases, neurological diseases, visual diseases, and coronary artery diseases. The response also couples the insulin and substrate induced postprandial surge in protein synthesis to the level of endoplasmic reticulum chaperones. In other work we studied expression of key glycolytic, gluconeogenic and nitrogen-metabolizing enzymes in CR and control mice. The results indicate that calorie restriction reduces hepatic but not muscle glycolysis, increases hepatic gluconeogenesis, and increases protein utilization for energy by extrahepatic tissues. Together, these data support the idea that CR enhances protein turnover and maintains this higher rate of turnover into old age. These effects likely stimulate protein renewal in old animals. This effect may be one of the key mechanisms for the anti-aging effects of CR. The metabolic changes with CR are similar to changes in hibernating mammals and in the life-span-extending dauer larval stage of C. elegans. Our work suggests that broadly similar hibernation-like states linked to nutritional stress and life span are very widespread in nature, and share many common features of insulin signaling systems.
Member, Research Planning Advisory Group, National Institute on Aging, 1998-1999
Molecular Biology and Biomedical Research. Topics of interest: Molecular basis of aging, Interactions between diet, health and longevity at the molecular level
Dhahbi, J.M., Mote, P.L., Wingo, J., Rowley, B.C., Cao, S.X., Walford, R.L., and Spindler, S.R. Energy Restriction alters gluconeogenic, gluconeogenic, glycolytic and nitrogen-metabolizing enzyme responses to food deprivation and feeding in mice. Submitted.