Office: 335 Linus Pauling Science Center
Telephone: (541) 737-5083
Fax: (541) 737-5077
Email Address: email@example.com
Mailing/Express Delivery Address:
Tory Hagen, Ph.D.
Linus Pauling Institute
Oregon State University
307 Linus Pauling Science Center
Corvallis, OR 97331
Our research seeks to identify the mode of action of two “age-essential” micronutrients, lipoic acid (LA) and acetyl-Lcarnitine (ALCAR). This work is aligned with Dr. Pauling’s concept of “orthomolecular medicine”—varying the concentrations of substances normally present in the body to affect health. We are using LA and ALCAR as “keys” to unlock important mechanisms associated with the basic biology of aging, which may lead to effective therapies for a number of age-related diseases and enhance the quality of life. We found that ALCAR and LA improve two of the most important cellular lesions of aging: the inability to respond to oxidative and toxicological challenges and the loss of mitochondrial function. Feeding old rats LA markedly elevates both cellular ascorbic acid and glutathione levels and induces Phase II detoxification enzymes, which markedly decline with age. LA appears to improve stress-response mechanisms by activating a transcription factor, Nrf2, enabling it to again bind to DNA sequences called the “Antioxidant Response Element” (ARE) found in over 200 genes involved in protecting cells against oxidative and toxicological insults. We are currently exploring why these stress response mechanisms decline with age and are focusing on cellular signaling pathways that LA may induce to activate Nrf2-mediated gene expression.
We found that ALCAR and LA, when fed to old rats, markedly improve many indices of mitochondrial decay. Mitochondria may be the “Achilles’ heel” of cellular aging because their dysfunction adversely affects conversion of dietary fuels into useful energy, dysregulates cellular calcium levels, increases oxidative stress, and limits tissue renewal. Our goal is to determine whether these age-essential micronutrients can improve human health by maintaining mitochondrial function.
We are also interested in defining how LA and ALCAR improve such seemingly distinct aging lesions as mitochondrial decay and lost stress-response mechanisms. We have evidence that these compounds synergistically regulate the metabolism of an enigmatic class of biomolecules called sphingolipids, which may be involved in both the age-related loss of Nrf2-mediated gene expression and mitochondrial decay. Identification that sphingolipids are part of these aging deficits opens the possibility for new therapies to improve human healthspan.
|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
|2003-2008||Principal Investigator, Linus Pauling Institute,
Oregon State University, Corvallis, OR
Associate Professor, Department of Biochemistry and Biophysics, OSU
|2008-present||Principal Investigator, Linus Pauling Institute,
Oregon State University, Corvallis, OR
Professor, Department of Biochemistry and Biophysics, OSU
The American Chemical Society
The Oxygen Society
Sigma Xi Honor Society
|2000-2005||Research Grant, NIA/NIH, "Dietary Prevention of Cardiac Mitochondrial Aging"|
|2003-2013||Research Grant, NCCAM/NIH, CER on CAM Antioxidant Therapies (CERCAT), Project Leader, "Lower Vulnerability to Toxins in Aging by Treatment with Lipoic Acid"|
|2007-2012||Research Grant, NIA/NIH, "Dietary Prevention of Cardiac Mitochondrial Aging"|
Michels AJ, Hagen TM, and Frei B. (2010) A new twist on an old vitamin: human polymorphisms in the gene encoding the sodium-dependent vitamin C transporter 1. Am J Clin Nutr 92:271-272.
Monette JS, Gómez LA, Moreau RF, Bemer BA, Taylor AW, and Hagen TM. (2010) Characteristics of the rat cardiac sphingolipid pool in two mitochondrial subpopulations. Biochem Biophys Res Commun 398:272-277.
Widlansky ME, Wang J, Shenouda SM, Hagen TM, Smith AR, Kizhakekuttu TJ, Kluge MA, Weihrauch D, Gutterman DD, and Vita JA. (2010) Altered mitochondrial membrane potential, mass, and morphology in the mononuclear cells of humans with type 2 diabetes. Transl Res 156:15-25.
Li L, Smith A, Hagen TM, and Frei B. (2010) Vascular oxidative stress and inflammation increase with age: ameliorating effects of alpha-lipoic acid supplementation. Ann N Y Acad Sci 1203:151-159.
Monette JS, Gómez LA, Moreau RF, Dunn KC, Butler JA, Finlay LA, Michels AJ, Shay KP, Smith EJ, Hagen TM. (2011) (R)-α-Lipoic acid treatment restores ceramide balance in aging rat cardiac mitochondria. Pharmacol Res 63:23-29.
Visioli F, Hagen TM. (2011) Antioxidants to enhance fertility: role of eNOS and potential benefits. Pharmacol Res 64:431-417.
Finlay LA, Michels AJ, Butler JA, Smith EJ, Monette JS, Moreau RF, Petersen SK, Frei B, Hagen TM. (2011) R-α-lipoic acid does not reverse hepatic inflammation of aging, but lowers lipid anabolism, while accentuating circadian rhythm transcript profiles. Am J Physiol Regul Integr Comp Physiol 302:R587-597
Shenvi SV, Smith E, Hagen TM. (2012) Identification of age-specific Nrf2 binding to a novel antioxidant response element locus in the Gclc promoter: a compensatory means for the loss of glutathione synthetic capacity in the aging rat liver? Aging Cell 11:297-304.
Albright RK, Goska BJ, Hagen TM, Chi MY, Cauwenberghs G, Chiang PY. (2011) OLAM: A wearable, non-contact sensor for continuous heart-rate and activity monitoring. Conf Proc IEEE Eng Med Biol Soc 2011:5625-5628.
Gómez LA, Heath SH, Hagen TM. (2012) Acetyl-l-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the l-carnitine content in the rat heart. Mech Ageing Dev 133:99-106.
Gómez LA, Hagen TM. (2012) Age-related decline in mitochondrial bioenergetics: does supercomplex destabilization determine lower oxidative capacity and higher superoxide production? Semin Cell Dev Biol 23:758-767.
Shay KP, Michels AJ, Li W, Kong AN, Hagen TM. (2012) Cap-independent Nrf2 translation is part of a lipoic acid-stimulated detoxification stress response. Biochim Biophys Acta 1823:1102-1109.
Keith DJ, Butler JA, Bemer B, Dixon B, Johnson S, Garrard M, Sudakin DL, Christensen JM, Pereira C, Hagen TM. (2012) Age and gender dependent bioavailability of R- and R,S-α-lipoic acid: a pilot study. Pharmacol Res 66:199-206.
Michels AJ, Hagen TM, Frei B. (2013) Human genetic variation influences vitamin C homeostasis by altering vitamin C transport and antioxidant enzyme function. Annu Rev Nutr [Epub ahead of print].