Office: 571 Weniger Hall
Telephone: (541) 737-5083
Fax: (541) 737-5077
Email Address: tory.hagen@oregonstate.edu
Mailing/Express Delivery Address:
Tory Hagen, Ph.D.
Linus Pauling Institute
Oregon State University
571 Weniger Hall
Corvallis, OR 97331-6512
| 1983 | B.S., Biochemistry, North Carolina State University, Raleigh, NC |
| 1989 | Ph.D., Biochemistry, Emory University, Atlanta, GA |
| 1989-1990 | Post-doctoral Fellow, Department of Biochemistry, Emory University, Atlanta, GA |
| 1990-1994 | Post-doctoral Fellow, Department of Molecular and Cell Biology, University of California, Berkeley, CA |
| 1994-1998 | Assistant Specialist Research Scientist, Department of Molecular and Cell Biology, University of California, Berkeley, CA |
| 1998-2003 | Principal Investigator, Linus
Pauling Institute, Oregon State University, Corvallis, OR Assistant Professor, Department of Biochemistry and Biophysics, OSU |
| 2003-present | Principal Investigator, Linus Pauling Institute,
Oregon State University, Corvallis, OR Associate Professor, Department of Biochemistry and Biophysics, OSU |
The American Chemical Society
The Oxygen Society
Sigma Xi Honor Society
| 1982-1983 | R.J. Reynolds Apprentice Scholarship |
| 1982-1983 | Elected Representative, Agri-Life Council, North Carolina State University |
| 1983 | North Carolina State University Biochemistry Award |
| 1986-1987 | Grant-in-Aid Award, Sigma Xi, Scientific Honor Society |
| 1990-1992 | NRSA Post-doctoral Fellowship, National Institutes of Health |
| 1995-1996 | Research Grant, Sandoz Foundation for Gerontological Research |
| 2000-2005 | Research Grant, NIA/NIH, "Dietary Prevention of Cardiac Mitochondrial Aging" |
| 2003-2008 | Research Grant, NCCAM/NIH, CER on CAM Antioxidant Therapies (CERCAT), Project Leader, "Lower Vulnerability to Toxins in Aging by Treatment with Lipoic Acid" |
Aging is an inevitable process that results from numerous adverse changes in the body. While people are generally resigned to eventually dying, there is almost a universal desire to "age gracefully," i.e., to maintain a high quality of life without debilitating health problems. Currently, little is known about the underlying events that cause us to age, although it appears that free radicals, which are produced in our cells as by-products of normal metabolism, may be an important underlying factor in the aging process. This lack of understanding of the events leading to aging does not currently support preventative measures that may slow the deleterious effects of aging, and only allows medical intervention after adverse health conditions have occurred. It is clear that research aimed at understanding the fundamental events in the aging process may eventually lead to effective therapies for a number of age-related diseases (cancer, heart disease, Alzheimer's disease, etc.) and hopefully provide a better quality of life.
Two projects are underway in the laboratory, which seek to i) define the mechanisms of mitochondrial decay in the aging heart and ii) elucidate the mechanisms leading to increased vulnerability to oxidative and xenobiotic insults in the elderly.
Mitochondria are the cell's "power plant," which converts raw fuels (food) into useful energy for the body. They also play major roles in calcium homeostasis and in regulating cellular apoptotic mechanisms (programmed cell death) and tissue renewal. Thus, any impairment in mitochondrial function could have dire consequences to the cell. We have shown that mitochondria become severely impaired with age. This impairment results in high levels of free radicals that not only continually damage the mitochondria, but other important parts of the cell (DNA), leading to a vicious downward spiral in overall cell function.
Specifically, we are examining mitochondrial decay with respect to age-related loss of cardiac function, the leading cause of morbidity and mortality in the elderly. Recently, we showed that mitochondrial decay is not uniform in the aging rat heart where mitochondria intercalated along the myofibrils (interfibrillary mitochondria; IFM) become dysfunctional while those associated with the sarcolemma (subsarcolemmal mitochondria; SSM) remain intact. In part, this decay resembles that seen in uncontrolled diabetes mellitus. Moreover, we also show that IFM accumulate free fatty acids and ceramides, which can aberrantly activate signaling pathways and contribute to cardiac dysfunction and death. Considering myocyte loss is extensive in the aging heart and also the most important underlying factor for congestive heart failure, identification of this asymmetric mitochondrial dyslipidemia will aid in designing important therapies to prevent IFM-induced cardiotoxicity in the elderly.
More importantly, we have identified certain compounds normally found in cells that decline markedly with age, but can be replenished through dietary supplementation. We have termed these compounds "age-essential" micronutrients and have shown that two of these compounds, acetyl-L-carnitine and lipoic acid, when fed to rats, markedly improve mitochondrial function and ameliorate many signs of aging. It is now our goal to determine whether these age-essential micronutrients can also improve human health.
Our other project involves an appreciated but under-researched aspect of aging, namely, the profound increased susceptibility to a variety of oxidative and xenobiotic insults. For this, we found that glutathione (GSH), a major cellular detoxicant, declines markedly with age. This loss is due to an age-dependent attenuation in activity and levels of gamma-glutamylcysteine ligase (GCL), the rate-controlling enzyme for GSH synthesis. Both basal and inducible GCL expression is controlled by Nrf2, a transcription factor that binds to the Antioxidant Response Element in its 5’ untranslated region. We now have evidence that Nrf2-dependent gene transcription becomes dysregulated with age, resulting in loss of GCL expression and potentially many of the nearly 400 other detoxication enzymes also controlled by this transcription factor. However, treatment with (R)-alpha-lipoic acid (LA) and other dithiol compounds re-regulates Nrf2-mediated gene expression, thereby increasing GSH levels and the ability to withstand oxidative insult. Our ongoing research seeks to define the exact mechanism(s) leading to Nrf2-mediated transcriptional dysregulation with age and also how LA acts to increase resistance to environmental toxins in the elderly.
We now have evidence that mitochondrial-induced accumulation of ceramides may also be partly responsible for the decline in Nrf2-mediated gene transcription. This is due to a ceramide-dependent chronic activation of phosphatases (PP2A and PP1), which result in lower Nrf2 phosphorylation and subsequently, its nuclear translocation. Thus, our two seemingly distinct projects may be intertwined.
Suh J.H., Moreau, R., Heath, S-H., and Hagen, T.M. (2005) Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Rep.10, 52-60.
Moreau, R., Nguyen, B.T., Doneanu, C.E., and Hagen, T.M. (2005) Reversal by aminoguanidine of the age-related increase in glycoxidation and lipoxidation in the cardiovascular system of Fischer 344 rats. Biochem. Pharmacol. 69, 29-40.
Marley, K., Mooney, D.T., Clark-Scannell, G., Tong, T.T., Watson, J., Hagen, T.M., Stevens, J.F., and Maier, C.S. (2005) Mass tagging approach for mitochondrial thiol proteins. J. Proteome Res. 4, 1403-1412.
Robinson, K.M., Janes, M.S., Pehar, M., Monette, J.S., Ross, M.F., Hagen, T.M., Murphy, M.P., and Beckman, J.S. (2006) Selective fluorescent imaging of superoxide in vivo using ethidium-based probes. Proc. Natl. Acad. Sci. U.S.A. 103, 15038-15043.
Smith, A.R., Visioli, F., and Hagen, T.M. (2006) Plasma membrane-associated endothelial nitric oxide synthase and activity in aging rat aortic vascular endothelia markedly decline with age. Arch. Biochem. Biophys. 454, 100-105.
Smith, A.R., Visioli, F., Frei, B., and Hagen, T.M. (2006) Age-related changes in endothelial nitric oxide synthase phosphorylation and nitric oxide dependent vasodilation: evidence for a novel mechanism involving sphingomyelinase and ceramide-activated phosphatase 2A. Aging Cell 5, 391-400.
McMackin, C.J., Widlansky, M.E., Hamburg, N.M., Huang, A.L., Weller, S., Holbrook, M., Gokce, N., Hagen, T.M., Keaney, J.F., and Vita J.A. (2007) Effect of combined treatment with alpha-lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease. J. Clin. Hypertens. 9, 249-255.
Milgram, N.W., Araujo, J.A., Hagen, T.M., Treadwell, B.V., and Ames, B.N. (2007) Acetyl-L-carnitine and alpha-lipoic acid supplementation of aged beagle dogs improves learning in two landmark discrimination tests. FASEB J. 21, 3756-3762.
Pehar, M., Vargas, M.R., Robinson, K.M., Cassina, P., Díaz-Amarilla, P.J., Hagen, T.M., Radi, R., Barbeito, L., and Beckman, J.S. (2007) Mitochondrial superoxide production and nuclear factor erythroid 2-related factor 2 activation in p75 neurotrophin receptor-induced motor neuron apoptosis. J. Neurosci. 27, 7777-7785.
Visioli F. and Hagen T.M. (2007) Nutritional strategies for healthy cardiovascular aging: focus on micronutrients. Pharmacol. Res. 55, 199-206.
Bogani, P., Canavesi, M., Hagen, T.M., Visioli, F., and Bellosta, S. (2007) Thiol supplementation inhibits metalloproteinase activity independent of glutathione status. Biochem. Biophys. Res. Commun. 363, 651-655.
Zhang, W.J., Bird, K.E., McMillen, T.S., Leboeuf, R.C., Hagen, T.M., and Frei B. (2008) Dietary alpha-lipoic acid supplementation inhibits atherosclerotic lesion development in apolipoprotein E deficient and apolipoprotein E/low-density lipoprotein receptor deficient mice. Circulation 117, 421-428.
Dixon, B.M., Heath, S.H., Kim, R., Suh, J.H., and Hagen TM. (2008) Assessment of endoplasmic reticulum glutathione redox status is confounded by extensive ex vivo oxidation. Antioxid Redox Signal. 10, 963-972.
