Principal Investigator and Helen P. Rumbel Professor for Healthy Aging Research, Linus Pauling Institute
Professor, Department of Biochemistry and Biophysics
Office: 335 Linus Pauling Science Center
Email Address: firstname.lastname@example.org
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
Smith EJ, Shay KP, Thomas NO, Butler JA, Finlay LF, Hagen TM. (2015) Age-related loss of hepatic Nrf2 protein homeostasis: Potential role for heightened expression of miR-146a. Free Radic Biol Med 89:1184-1191.
Keith D, Finlay L, Butler J, Gómez L, Smith E, Moreau R, Hagen T. (2014) Lipoic acid entrains the hepatic circadian clock and lipid metabolic proteins that have been desynchronized with advanced age. Biochem Biophys Res Commun 450:324-329.
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 33:45-70.
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.
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.
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.
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.
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.
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.
Visioli F, Hagen TM. (2011) Antioxidants to enhance fertility: role of eNOS and potential benefits. Pharmacol Res 64:431-417.
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.