Individual Listing

5478 BOYCE HALL
University of California
Riverside, CA 92521

Spindler, Stephen R

Professor Of Biochemistry & Biochemist

College of Natural and Agricultural Sciences

Biochemistry


Biography

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.

Degrees

PhD Biochemistry 1976

University of Texas at Houston

Awards

Member, Research Planning Advisory Group, National Institute on Aging, 1998-1999
Member, Physiological Sciences Study Section, NIH 1992-1995
RFA-Genetic and Molecular Basis of Aging Study Section, NIH, 1993
Site Visit Scientific Review Committee and Study section, NIH, 1991 (2), 1990, & 1987
NIH Postdoctoral Fellow, 1980-1981
Ad Hoc Review Committee, NIH, 1990; Ad Hoc Member
Endocrinology Study Section, NIH, 1990, 1988
PHS Predoctoral Trainee, 1972-1976


Research Area

Molecular Biology and Biomedical Research. Topics of interest: Molecular basis of aging, Interactions between diet, health and longevity at the molecular level

Publications

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.

Dhahbi, J.M., Cao, S.X., Tillman, J.B., Mote, P.L., Madore, M., Walford, R.L., and Spindler, S.R. Increase in the rate and extent of hepatic protein secretion by dietary calorie restriction. Submitted.

Dhahbi, J.M., Mote, P.L., Wingo, J., Walford, R.L., and Spindler, S.R. Dietary calories and age regulate genes of hepatic gluconeogenesis and glycolysis and muscle protein turnover. J. Physiology, In press.

Thompson, P.D., Hsieh, J.C., Whitfield, G.K., Haussler, C.A., Jurutka, P.W., Galligan, M.A., Tillman, J.B., Spindler, S.R., Haussler, M.R. The vitamin D receptor displays DNA binding and transactivation as a heterodimer with the retinoid X receptor, but not with the thyroid hormone receptor. J. Cell. Biochem., In press.

Mote, P.L., Tillman, J.B., and Spindler, S.R. Glucose regulation of GRP78 expression. Mech. Ageing Dev. 104: 149-158 (1998).

Dhahbi, J.M., Tillman, J.B., Cao, X., Mote, P.L., Walford, R.L., and Spindler, S.R. Caloric intake alters the efficiency of catalase mRNA translation in the liver of old female mice, J. Gerontology: Biological Sciences 53A: B180-B185 (1998).

Dhahbi, J.M., Mote, P.L., Tillman, J.B., Walford, R.L., and Spindler, S.R. Tissue-specific regulation of endoplasmic reticulum chaperones by dietary energy restriction in mice J. Nutr. 127: 1758-1764 (1997).

Walford, R.L. and Spindler, S.R. The response to calorie restriction in mammals is part of a broad spectrum of adaptive responses which include hibernation: A cross-adaptation hypothesis J. Gerontology, 52: B179-B183 (1997).

Tillman, J.B., Mote, P.L., Dhahbi, J.M., Walford, R.L., and Spindler, S.R. Dietary energy restriction in mice negative regulates hepatic glucose regulated protein 78 (GRP78) expression at the posttranscriptional level J. Nutr., 126: 416-423 (1996).

Tillman, J.T., Dhahbi, J.M., Mote, P.L., Walford, R.L., and Spindler, S.R. Dietary calorie restriction in mice induces carbamyl phosphate synthetase I gene transcription tissue specifically, J. Biol. Chem. 271: 3500-3506 (1996).

Tillman, J.B., Mote, P.L., Walford, R.L., and Spindler, S.R. Structure and regulation of the mouse GRP78 (BiP) promoter by glucose and calcium ionophore Gene 158: 225-229 (1995).

Force, W.F. and Spindler, S.R. T3 3,5,3'-L-triiodothyronine (thyroid hormone)-induced protein-DNA interactions in the thyroid hormone response elements and cell type-specific elements of the rat growth hormone gene revealed by in vivo dimethyl sulphate footprinting J. Biol. Chem. 269:9682-9686 (1994).

Force, W.F., Tillman, J.T., Sprung, C.N., and Spindler, S.R. Homodimer and heterodimer DNA binding and transcriptional responsiveness to triiodothyronine (T3) and 9-cis retinoic acid are determined by the number and order of high affinity half-sites in a T3 response element J. Biol. Chem. 269: 8863-8871 (1994).