Dr. Stephen R. Spindler
Professor of Biochemistry
Molecular Biology - Biomedical Research

Ph.D., University of Texas at Houston, 1976
PHS Predoctoral Trainee
NIH Postdoctoral Fellow
Past Member, NIH Physiological Sciences Study Section

CONTACT
Phone : (951) 827-3553
Fax : (951) 827-4434
e-mail : spindler@ucrac1.ucr.edu
RESEARCH INTERESTS
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 caloric restriction. The positive relationship between caloric restriction, health and longevity has been found from mammals to insects to worms.

CR has been viewed as less effective in older animals and as acting incrementally to slow or prevent age-related changes in gene expression. However, we found that mice who begin CR in late middle-age reap its benefits almost immediately. Similar results have also been reported in fruit flies. In our studies, when CR was begun late in life, lifespan was still extended by about six months and CR produced a delay in deaths due to cancer, perhaps by decreasing the rate of tumor growth. Mice put on this diet late in life developed the same patterns of liver gene expression as those who began CR in their youth. Also, when the mice were taken off CR, they returned to their previous patterns of gene expression rapidly. Because liver cancer is the most common cause of death in these mice, the results suggest a cause and effect relationship between dietary calories, the rate of aging, and liver gene expression patterns. No previous study has tied these together so closely in a mammal. The results go against prevailing theories that say slow, incremental changes in gene expression and metabolism are the major cause of aging. They also indicate that many of the important effects of caloric restriction on health begin very rapidly after the onset of the diet. The key genomic effects of CR appear to be rapid, readily reversible, and do not seem to result from the long-term accrual of irreversible molecular damage. Drug therapies that induce the same patterns of gene activity seem likely to produce the same age-retarding effects.

We also have performed other genome-wide gene-expression studies in mice with disrupted growth hormone-insulin-like growth factor-1 signaling (DF) that were either CR or given free access to food. Others have shown that either DF or CR alone can extend lifespan, and that together they act additively to extend the lifespan of mice even more. We found that CR and DF additively affected the expression of a group of genes. Individually and together, DF and CR independently affected the expression of other groups of genes. These results indicate that DF and CR affect overlapping sets of genes, and additively affect a subset of genes associated with enhanced longevity. They produced changes in gene expression consistent with increased insulin, glucagon and catecholamine sensitivity, gluconeogenesis, protein turnover, lipid beta-oxidation, apoptosis, and xenobiotic and oxidant metabolism; and decreased cell proliferation, lipid and cholesterol synthesis, and chaperone expression. These results provide a focused group of new genes which are important in regulating the lifespan of mammals, and which may be “drugable targets” for anti-aging therapeutics.

Finally, we investigated the effects of CR in mouse heart. Eight weeks of CR reproduced many of the long-term effects of CR on gene expression and physiology. CR rapidly decreased natriuretic peptide B and collagen I and III expression. CR reduced perivascular collagen accumulation and cardiomyocyte size in the left ventricle. These results suggest that hearts of LT-CR mice are physiologically younger than those of control mice. Switching CR mice to control feeding rapidly returned 91% of the CR responsive genes to control expression levels. Thus, CR rapidly and reversibly induced genomic changes associated with reduced cardiovascular pathology.

SELECTED PUBLICATIONS

See publications on PubMed

Dhahbi, J.M., Mote, P.L. and Spindler, S.R. Identification of potential calorie restriction mimetics by microarray profiling. Cell Aging, Submitted.

Spindler, S.R. Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction. Mechanisms of Aging and Development. 31 May 2005. Epub ahead of print (2005).

Dhahbi, J.M., Tsuchiya, T., Kim, H.J., Mote, P.L. and Spindler, S.R. Myocardial Genomic and Phenotypic Responses to Short- and Long-term Changes in Caloric Intake. Journal of Gerontology, Biological Sciences. In Press (2005).

Tsuchiya, T., Dhahbi, J.M., Cui, X., Mote, P.L., Bartke, A. and Spindler, S.R. Additive regulation of hepatic gene expression by dwarfism and caloric restriction . Physiological Genomics, 19, 307-315 (2004); Epub 2004 Mar 23.

Dhahbi, J.M., Kim, H.J., Mote, P.L. and Spindler, S.R. Temporal linkage between the physiologic and genomic responses to caloric restriction. Proc. Natl. Acad. Sci. USA. 101, 5524-5529 (2004); Epub 2004 Mar 25.

Dhahbi, J.M., Mote, P.L., Cao, S.X., and Spindler, S.R. Hepatic Gene Expression Profiling of Streptozotocin-Induced Diabetes. Diabetes Technology & Therapeutics, 5, 411-420 (2003).

Spindler, S.R. and Dhahbi, J.M. Protein Turnover, Energy Metabolism, Aging and Caloric Restriction. In, Energy Metabolism and Lifespan Determination: Advances in Cell Aging and Gerontology Vol. 14, Mattson, M.P., ed., Elsevier, Amsterdam , The Netherlands , pp. 69-86 (2003).

Dhahbi, J.M., Cao, S.X., Mote, P.L., Wingo, J., Rowley, B.C., and Spindler, S.R. Postprandial induction of chaperone gene expression is rapid in mice. J. Nutr., 132, 31-37 (2002).

Cao, S.X., Dhahbi, J.M., Mote, P.L., and Spindler, S.R. Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proc. Natl. Acad. Sci., USA 98, 10630-10635 (2001).

Dhahbi, J.M. and Spindler, S.R. Aging of the liver. In, 'Biology of Aging and its Modulation, Vol. 3: Aging of Organs and Systems', Aspinall, R., ed., Kluwer Academic Publisher, Dordrecht , The Netherlands , pp. 271-291 (2003).

AWARDS AND HONORS
Chair, Department of Biochemistry, UCR, 1998-2001; 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; Ad Hoc Review Committee, NIH, 1990; Ad Hoc Member, Endocrinology Study Section, NIH, 1990, 1988; NIH Postdoctoral Fellow, 1980-1981; PHS Predoctoral Trainee, 1972-1976
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