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, including nonhuman primates. The primary focus of my research is to identify critical factors involved in the mechanisms of delayed aging by caloric restriction.
The inverse linear relationship between calorie intake and lifespan extension 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. Based on these observations, we have proposed that reprogramming of energy metabolism is a critical first step in the mechanisms of CR. We have described a novel mechanism for mitochondrial adaptation that links cellular survival and longevity through a common pathway that involves the key regulator of mitochondria, PGC-1α 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. The first project investigates the molecular basis of metabolic reprogramming induced by CR including the identification of key factors recruited to implement delayed aging. The second focuses on lipid metabolism in aging of skeletal muscle and the role of adipose-tissue secreted factors in dictating the rate of aging. The third focuses on the aging brain and the role of metabolism in age-related neurodegenerative disease.
Miller, K. N., Burhans, M. S., Clark, J. P., Howell, P. R., Polewski, M. A., DeMuth, T. M., Eliceiri, K. W., Lindstrom, M. J., Ntambi, J. M., & Anderson, R. M. (2017). Aging and caloric restriction impact adipose tissue, adiponectin, and circulating lipids. Aging Cell. Advance online publication.
View publication via DOI: DOI:10.1111/acel.12575
Mattison, J. A., Colman, R. J., Beasley, T. M., Allison, D. B., Kemnitz, J. W., Roth, G. S., Ingram, D. K., Weindruch, R., de Cabo, R., & Anderson, R. M. (2017). Caloric restriction improves health and survival of rhesus monkeys. Nature Communications, 8, 14063.
View publication via DOI: DOI:10.1038/ncomms14063
Balasubramanian, P., Mattison, J. A., & Anderson, R. M. (2017). Nutrition, metabolism, and targeting aging in nonhuman primates. Ageing Research Reviews. Advance online publication.
View publication via DOI: DOI:10.1016/j.arr.2017.02.002
Martin, S.A., DeMuth, T.M., Miller, K.N., Pugh, T.D., Polewski, M.A., Colman, R.J., Eliceiri, K.W., Beasley, T.M., Johnson, S.C., & Anderson, R.M. (2016). Regional metabolic heterogeneity of the hippocampus is non-uniformly impacted by age and caloric restriction. Aging Cell, 15: 100.
View publication via DOI: DOI:10.1111/acel.12418
Burhans, M. S., Flowers, M. T., Harrington, K. R., Bond, L. M., Guo, C. A., Anderson, R. M., & Ntambi, J. M. (2015). Hepatic oleate regulates adipose tissue lipogenesis and fatty acid oxidation. Journal of Lipid Research, 56(2), 304-318.
View publication via DOI: DOI:10.1194/jlr.M054429
Barger, J. L., Anderson, R. M., Newton, M. A., da Silva, C., Vann, J. A., Pugh, T. D., Someya, S., Prolla, T. A., & Weindruch, R (2015). A conserved transcriptional signature of delayed aging and reduced disease vulnerability is partially mediated by SIRT3. PLoS One, 10(4), e0120738.
View publication via DOI: DOI:10.1371/journal.pone.0120738
Polewski, M.A., Burhans, M.S., Zhao, M., Colman, R.J., Shanmuganayagam, D., Lindstrom, M.J., Ntambi, J.M., & Anderson, R.M. (2015). Plasma diacylglycerol composition is a biomarker of metabolic syndrome onset in rhesus monkeys. Journal of Lipid Research, 56:1461.
View publication via DOI: DOI:10.1194/jlr.M057562
Starks, E.J., O'Grady, P., Hoscheidt, S.M., Racine, A.M., Carlsson, C.M., Zetterberg, H., ... Okonkwo, O.C., Puglielli, L., Asthana, S., ... Anderson, R., ... Sager, M.A., Johnson, S.C., Bendlin, B.B. (2015). Insulin resistance is associated with higher cerebrospinal fluid tau levels in asymptomatic APOE Ε4 carriers. Journal of Alzheimer's Disease, 46(2), 525-33.
View publication via DOI: DOI:10.3233/JAD-150072
Colman, R.J., Beasley, T.M., Kemnitz, J.W., Johnson, S.C., Weindruch, R., & Anderson, R.M. (2014). Caloric restriction increases age-related and all cause survival in rhesus monkeys. Nature Communications 5, 3557.
View publication via DOI: DOI:10.1038/ncomms4557
Lamming, D. W., & Anderson, R. M. (2014). Metabolic effects of caloric restriction. In eLS: Encyclopedia of Life Sciences. John Wiley & Sons, Ltd..
View publication via DOI: DOI:10.1002/9780470015902.a0021316.pub2
Sridharan, A., Pehar, M., Salamat, M. S., Pugh, T. D., Bendlin, B. B., Willette, A. A., Anderson, R. M., Kemnitz, J. W., . . . Weindruch, R., Puglielli, L., & Johnson, S. C. (2013). Calorie restriction attenuates astrogliosis but not amyloid plaque load in aged rhesus macaques: A preliminary quantitative imaging study. Brain Research, 1508, 1-8.
View publication via DOI: DOI:10.1016/j.brainres.2013.02.046
Yamada, Y., Colman, R. J., Kemnitz, J. W., Baum, S. T., Anderson, R. M., Weindruch, R., & Schoeller, D. A. (2013). Long-term calorie restriction decreases metabolic cost of movement and prevents decrease of physical activity during aging in rhesus monkeys. Experimental Gerontology, 48(11), 1226-1235.
View publication via DOI: DOI:10.1016/j.exger.2013.08.002
Pugh, T. D., Conklin, M. W., Evans, T. D., Polewski, M. A., Barbian, H. J., Pass, R., . . . Weindruch, R., . . . Anderson, R. M. (2013). A shift in energy metabolism anticipates the onset of sarcopenia in rhesus monkeys. Aging Cell, 12(4), 672-681.
View publication via DOI: DOI:10.1111/acel.12091
Anderson, R. M., & Weindruch, R. (2012). The caloric restriction paradigm: Implications for healthy human aging. Am J Hum Biol, 24(2), 101-106.
View publication via DOI: DOI:10.1002/ajhb.22243
Csiszar, A., Sosnowska, D., Tucsek, Z., Gautam, T., Toth, P., Losonczy, G., . . . Weindruch, R., Anderson, R. M., & Sonntag, W. E.Ungvari, Z. (2012). Circulating factors induced by caloric restriction in the nonhuman primate macaca mulatta activate angiogenic processes in endothelial cells. Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 68(3), 235-249.
View publication via DOI: DOI:10.1093/gerona/gls158
McKiernan, S. H., Colman, R. J., Aiken, E., Evans, T. D., Beasley, T. M., Aiken, J. M., . . . Weindruch, R., & Anderson, R. M. (2012). Cellular adaptation contributes to calorie restriction-induced preservation of skeletal muscle in aged rhesus monkeys. Experimental Gerontology, 47(3), 229-236.
View publication via DOI: DOI:10.1016/j.exger.2011.12.009
McKiernan, S. H., Colman, R. J., Lopez, M., Beasley, T. M., Aiken, J. M., Anderson, R. M., & Weindruch, R. (2011). Caloric restriction delays aging-induced cellular phenotypes in rhesus monkey skeletal muscle. Experimental Gerontology, 46(1), 23-29.
View publication via DOI: DOI:10.1016/j.exger.2010.09.011
Anderson, R.M., & Weindruch, R. (2010). Metabolic reprogramming, caloric restriction and aging. Trends in Endocrinology and Metabolism, 21(3), 134-141.
Click here to download this publication.
View publication via DOI: DOI:10.1016/j.tem.2009.11.005
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.
Click here to download this publication.
View publication via DOI: DOI:10.1126/science.1173635
Anderson, R.M., Shanmuganayagam, D., & Weindruch, R. (2009). Caloric restriction and aging: Studies in mice and monkeys. Toxicologic Pathology, 37(1), 47-51.
View publication via DOI: DOI:10.1177/0192623308329476
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.
View publication via DOI: DOI:10.1111/j.1474-9726.2007.00357.x
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.
View publication via DOI: DOI:10.1186/1471-2164-8-80
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.
View publication via DOI: DOI:10.1016/j.exger.2006.10.019
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.
View publication via DOI: DOI:10.2337/diacare.28.8.1954
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.
View publication via DOI: DOI:10.1126/science.1088697
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.
View publication via DOI: DOI:10.1074/jbc.M111773200
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.
View publication via DOI: DOI:10.1074/jbc.M205670200
Want to find more Publications? Click here to search the publication database