Healthy Aging Program

student working in the Healthy Aging Program laboratory

The goal of the Healthy Aging Program is to move geriatric medicine from reactively responding to disease, when it is costly and difficult to treat, to proactively discovering and substituting strategies that prolong healthspan by compressing morbidity and reducing mortality from chronic diseases. Fundamental research initiatives are aimed at understanding the “vitality assurance” processes at the cellular and molecular level that maintain health during aging, and discovering “age-essential” micronutrients and dietary regimens that can limit the risk for developing age-associated diseases.

Faculty involved: Kathy Magnusson, D.V.M, Ph.D.,  Tory M. Hagen, Ph.D.,  Joseph Beckman, Ph.D.,  Viviana Pérez, Ph.D., and Adrian Gombart, Ph.D.

Aging and Memory

Principal Investigator: Kathy Magnusson, D.V.M, Ph.D.

We’ve been characterizing changes in the expression of a receptor that is very important for the formation of memories, the N-methyl-D-aspartate (NMDA) receptor. This receptor uses glutamate as a transmitter. The NMDA receptor shows greater declines in binding of glutamate with increased age than any of the other glutamate receptors. We’ve found relationships between NMDA receptor binding and expressions of two NMDA receptor subunits, GluN2B (epsilon2, NR2B) and GluN2A (epsilon1, NR2A), during aging. We've also shown associations between age-related changes in NMDA-binding densities and subunit expressions and declines in both working and reference memory ability.

We are continuing to characterize the changes that occur in the NMDA receptor with increasing age. We are currently examining whether increasing the expression of the GluN2B subunit or some of the splice variants of the GluN1 subunit is beneficial to memory in aged animals, how aging affects where the NMDA receptors are located within the neurons, and whether inflammation plays a role in the effects of aging on NMDA receptors. We are also trying to determine exactly what role NMDA receptors in the prefrontal cortex play in different forms of memory. Ultimately, we want to discover the mechanisms underlying the age-related changes in the NMDA receptor.

The lab’s main goal is to find interventions into aging that will help to maintain the quality of life into old age. We’re also interested in helping to better understand the function of the NMDA receptor in different brain regions.

Aging, Stress Response, and Mitochondrial Decay

Principal Investigator: Tory M. Hagen, Ph.D.

Our research seeks to identify the mode of action of two “age-essential” micronutrients, lipoic acid (LA) and acetyl-L-carnitine (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.

Lou Gehrig's Disease (ALS), Peroxynitrite, and Superoxide Dismutase

Principal Investigator: Joseph Beckman, Ph.D.

Since 2002, I have served as Director of OSU’s Environmental Health Sciences Center, which is funded by the National Institutes of Health to support research on the role of the environment in causing disease. The Center provides advanced technology that supports LPI researchers with the long-term goal of understanding how we can reduce our susceptibility to environmental stress as we age.

A major research project in my laboratory is aimed at understanding how oxidative stress, superoxide dismutase, and zinc are involved in Lou Gehrig’s disease, also known as amyotrophic lateral sclerosis (ALS). ALS is a dreadful disease caused by the unexplained death of motor neurons that control the movement of all voluntary muscles. We have only about 500,000 motor neurons at birth that cannot be replaced. Mutations in the antioxidant enzyme superoxide dismutase are the first identified cause of ALS. Our research indicates that the loss of zinc from superoxide dismutase is what causes motor neurons to die. We have shown that supporting cells in the spinal cord called astrocytes are key to understanding why the disease progresses. We are also investigating other dietary supplements, such as lipoic acid, acetyl-L-carnitine, and alpha-tocopherol, as possible means to slow the progression of ALS.

The second major project in the laboratory focuses on the roles of nitric oxide, peroxynitrite, and nitrotyrosine in human disease. The major function of superoxide dismutase is to scavenge superoxide, which is an oxygen radical. Nitric oxide also has a “dark side” and, following reaction with superoxide to produce the powerful oxidant peroxynitrite, can promote oxidative and nitrative damage to blood vessels, skin, heart, lung, kidney, and brain. We are characterizing the role of peroxynitrite in injuring cells and how cells respond to this damage.

Rapamycin, Protein Homeostasis, and Aging

Principal Investigator: Viviana Pérez, Ph.D.

My primary area of research interest is the role of protein homeostasis in longevity, using a comparative biology approach. We previously found that the proteomes of long-lived species like the little brown bat and naked mole rat are more resistant to urea- and heat-induced unfolding than those of shorter-lived bats or mice. We have also shown more robust maintenance of the proteasome and lower levels of ubiquitinated proteins in old (20-yr) naked mole rats compared to old (3-yr) mice, suggesting that long-lived species might have evolved enhanced chaperone-like activities to preserve protein structure and prevent misfolding or aggregation. My laboratory is focused on establishing the role of proteostasis control in longevity by studying three important processes that alter protein homeostasis: protein aggregation, protein folding (chaperones), and protein degradation.

My second area of interest includes studies on dietary restriction (DR) and rapamycin. Both interventions extend lifespan and healthspan in rodents, and previous data suggest that rapamycin could be acting in a similar way to DR. To test this, I’m developing a study involving four different feeding groups of mice: ad libitum, DR, rapamycin, and rapamycin-DR. If rapamycin acts like DR, DR should not have any additional effect on lifespan in the rapamycin-DR group. The outcome of this study may have a big impact on the aging field, providing a better understanding of and new insights into the aging process and new prospects for the development of DR mimetics.

Vitamin D and Immune Function

Principal Investigator: Adrian Gombart, Ph.D.

Our research is focused on understanding the regulation of antimicrobial peptide expression by the vitamin D pathway. When immune cells called macrophages encounter a pathogen and become activated, the vitamin D pathway is turned on, leading to the induction of the cathelicidin antimicrobial peptide if serum levels of vitamin D are sufficient. We have shown that this mechanism is conserved in humans and primates but not in other mammals. Therefore, we developed a transgenic mouse that carries the human cathelicidin gene. Using this model, we are testing the ability of vitamin D to protect against infection by influenza, Salmonella, and Mycobacterium tuberculosis. Vitamin D has been used to treat tuberculosis, and its deficiency is associated with increased risk of tuberculosis. This model will allow us to test the role of vitamin D and cathelicidin during initial infection, latency, and reactivation.

Another focus of our research is to identify additional dietary compounds that regulate the expression of the cathelicidin gene. This gene is also induced by sodium butyrate and lithocholic acid, which functions through the vitamin D receptor. Nutrients that bind the vitamin D receptor may modulate the immune system by inducing the cathelicidin gene. We discovered that curcumin in curry modestly induces expression of the cathelicidin gene, which could protect the gut from infection. In collaboration with colleagues at Cedars-Sinai Medical Center, we discovered that vitamin B3 (niacin) boosts killing of methicillin-resistant Staphylococcus aureus (MRSA) by white blood cells, in part, by increasing cathelicidin levels. A small molecule library is being screened for regulators of the cathelicidin gene. The identification of new regulatory compounds may give clues as to how the gene is regulated in vivo and lead to the identification of other nutrients that can be used to boost the immune system.

Finally, we are interested in determining the effect of vitamin D on the function of the innate immune system in the elderly. Aging is accompanied by low-grade, chronic, systemic inflammation, and vitamin D has important anti-inflammatory properties. We want to determine if sufficient levels of vitamin D will reduce the inflammatory phenotype. We also want to determine if reversing severe deficiency will raise cathelicidin protein levels in the blood, which may reduce mortality in kidney dialysis and sepsis patients.