Untitled Document

Research

Rozalyn Anderson

Ph.D., University College Dublin, Ireland
Assistant Scientist, Wisconsin National Primate Research Center
rmanderson5@wisc.edu

Nutrient sensitive regulatory pathways in aging and age-associated disease

Interest in the biology of aging has increased considerably in recent times and has prompted the demand for a better understanding of the underlying mechanisms. Despite the apparent phenotypic disparity across age-associated disorders including cancer, cardiovascular disease and diabetes, clues are emerging from the study of caloric restriction that may connect these disorders and illuminate the complexities of the aging process. Caloric restriction is a dietary regimen of reduced calorie intake without malnutrition which has been shown to delay aging and the onset of age-associated phenotypes in a broad range of species. The primary focus of my research is to identify critical factors involved in the mechanisms of aging retardation by caloric restriction.

The inverse linear relationship between calorie intake and lifespan suggests that factors involved in regulation of metabolism are likely to be important in the mechanism of lifespan extension. Indeed, aging is associated with loss of efficiency of energy metabolism, and reduced expression of nuclear encoded mitochondrial genes is a hallmark of aging in numerous species. These observations support a model where reprogramming of energy metabolism is a key component in the mechanisms of caloric restriction. We have recently described a novel mechanism for mitochondrial adaptation that links cellular survival and longevity through this common pathway. The activity of a key regulator of mitochondria, PGC-1α is regulated through changes in protein subcellular localization and stability. Two components of this regulatory pathway include the putative longevity regulator SIRT1, and the nutrient sensitive kinase GSK3β previously associated with Alzheimer�s Disease.

Our present work in cell culture, mouse, and primate models tests the involvement of this pathway in three areas:

� Metabolic reprogramming induced by caloric restriction in mice and primates

� The effect of age and caloric restriction on adiposity, metabolism and inflammation in adipose tissue

� Cellular proliferation, morphology and adhesion.

Representative Publications
Colman, R.J., Anderson, R.M., Johnson, S.C., Kastman, E.K., Kosmatka, K.J., T. Beasley, T.M., Allison, D.B., Cruzen, C., Simmons, H.A., Kemnitz, J.W., & Weindruch, R. (2009). Caloric restriction delays disease onset and mortality in rhesus monkeys. Science, 325, 201-204.

Anderson, R.M., Barger, J.L., Edwards, M.G., Braun, K.H., O�Connor, C.E., Prolla, T.A., & Weindruch, R. (2008). Dynamic regulation of PGC-1alpha localization and turnover implicates mitochondrial adaptation in longevity and the stress response. Aging Cell, 7, 10.

Edwards, M.G., Anderson, R.M., Yuan, M., Kendziorski, C., Weindruch, R., & Prolla, T.A. (2007). Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program. BMC Genomics, 8, 80.

Anderson, R.M., & Weindruch, R. (2007). Metabolic reprogramming in calorie restriction. In C.V. Mobbs, K. Yen, P.R. Hof., & A.G. Karger (Eds.), Mechanisms of calorie restriction in aging and disease (Interdisciplinary Topics in Gerontology) (Vol. 35, pp. 18-38). Switzerland.

Anderson, R.M., & Weindruch, R. (2006). Calorie Restriction: Progress during mid-2005 to mid-2006. Exp. Gerontology, 41, 1247-9.

Emanuele, N., Sacks, J., Klein, R., Reda, D., Anderson, R., Duckworth, W., & Abraira, C. (2005). Veterans Affairs Diabetes Trial Group. Ethnicity, race and baseline retinopathy correlates in the Veterans Diabetes Trial. Diabetes Care, 28(8), 1954-1958.

Anderson, R.M., & Sinclair, D.A. (2004). Yeast RecQ helicases: clues to DNA repair, genome stability and aging. In M. Lebel (Ed.), Werner Syndrome (pp. 78-106). Eurekah press.

Anderson, R.M., Latorre-Esteves, M., Neves, A.R., Lavu, S., Medvedik, O., Taylor, C., Howitz, K. T., Santos, H., & Sinclair, D.A. (2003). Yeast lifespan extension by calorie restriction is independent of NAD fluctuation. Science, 302, 2124-6.

Anderson, R.M., Bitterman, K.J., Wood, J.G, Medevdik, O., & Sinclair, D.A. (2003). Nicotinamide and Pnc1 govern lifespan extension by calorie restriction in S, cerevisiae. Nature, 423, 181.

Anderson, R.M, Bitterman, K., Wood, J., Medvedik, O., Cohen, H., Lin, S.S., Manchester, J.K., Gordon, J.I., & Sinclair, D.A. (2002). Manipulation of a nuclear NAD+ salvage pathway delays aging without altering steady-state NAD+ levels. J. Biol. Chem., 277, 18881-90.

Bitterman, K.J., Anderson, R.M., Cohen, H.Y., Latorre-Esteves, M., & Sinclair, D.A. (2002). Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast Sir2 and human SIRT1. J. Biol. Chem., 277, 45099-45107.

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