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Human Performance Clinical Research Laboratory - Health and Exercise Science

Human Performance Clinical Research Laboratory Areas of Research

Research Areas

Mitochondrial Biogenesis and Aging

Mitochondrial deterioration contributes to the aging process, while mitochondrial biogenesis slows the aging process and extends healthspan. Caloric restriction (CR) is the only intervention known to consistently increase lifespan and healthspan across a variety of species. CR stimulates AMP-activated protein kinase (AMPK) and inhibits the mammalian target of rapamycin (mTOR) with downstream effects on sestrin3 and FOXO transcription factors. These responses are indicative of an energetic stress, and in sum lead to global inhibition of protein synthesis to conserve energetic resources. Although controversial, it is thought that CR increases life/healthspan by increasing mitochondrial biogenesis. We have determined that mitochondrial protein synthesis (a direct measure of mitochondrial biogenesis) is maintained or increased during CR (see preliminary data) consistent with the idea that CR mediates its effects in part through increased mitochondrial biogenesis. Because mitochondrial protein synthesis is maintained or increased during CR when global protein synthesis is inhibited, there must be mechanisms to permit preferential translation of nuclear encoded mitochondrial proteins. Studies in yeast and drosophila indicate that mRNA sequence elements and sub-cellular localization can increase the translation of mitochondrial proteins, or make them resistant to the inhibition of cap-dependent translation. It currently is not known if similar mechanisms are at play in mammalian cells. The information gained from our research could aid in the development of CR mimetics or development of alternative therapeutic approaches to extend lifespan and healthspan.

Nrf2 and Stress Resistance

Redox imbalance is associated with most, if not all, chronic diseases. However, clinical trials using supplementation of exogenous antioxidants have been disappointing with little improvement in CVD outcomes. An alternative approach is to identify interventions that up-regulate endogenous antioxidants. Nuclear factor-E2-related factor 2 (Nrf2) is a transcription factor that mediates expression of endogenous antioxidants and many other proteins involved with regulation of cell cycle and cell death. Nrf2 dysregulation is associated with many chronic diseases including CVD. Enhancing endogenous antioxidant defenses via Nrf2 activation is a promising approach for promoting redox balance. Our long term goal is to understand the role of redox (im)balance in chronic disease. We have been working to identify the mechanism(s) of phytochemical induced Nrf2 activation, establish whether Nrf2 activation is essential for phytochemical induced protection against oxidant stresses relevant to chronic disease, and translate our in vitro observations of phytochemical induced protection against oxidative stress to in vivo models.

Nrf2 is the master regulator of the endogenous antioxidant response. Nrf2 is kept inactive by Kelch-like ECH-associated protein 1 (Keap1), which targets Nrf2 for poly-ubiquitination and rapid degradation. During redox imbalance, the Keap1-Nrf2 association is disrupted by oxidation of Keap1 thiol groups, leaving Nrf2 free to enter the nucleus. A second mechanism involves phosphorylation of Nrf2 by kinases with subsequent release from Keap1 and translocation to the nucleus. Once released from Keap1, Nrf2 binds the antioxidant response element (ARE) in various promoter regions, which increases the transcription of a variety of cytoprotective genes including phase II detoxification and antioxidant enzymes that promote cytoprotection.

Phytochemical compounds offer a potential means of activating Nrf2 without prior “oxidant stress”. We have worked with a phytochemical compound designed to stimulate the noninjurious pathway of Nrf2/ARE activation at low, pharmacologically attainable concentrations of each of the compounds used. The result is a remarkable level of synergy that greatly exceeds the sum of the contributions of the individual components with respect to Nrf2 activation.

As part of the National Institute of Aging Interventions Testing Program we proposed that a Nrf2 activator is a treatment that could potentially increase lifespan. The completed study demonstrated that lifelong treatment with a Nrf2 activator increased lifespan in male mice. Follow-up studies are planned to expand on this exciting result.

Protein Turnover, Cellular Proliferation and Aging

Protein damage is a hallmark of the aging process. We have taken an interest in a variety of models of slowed aging including dietary (caloric restriction), behavioral (exercise), pharmaceutical (rapamycin), genetic (dwarf mouse) or naturally long-lived species (bivalves). It is hoped that by studying these models we can determine different strategies to maintain protein integrity in a variety of tissues. Currently we are exploring how protein synthesis of key proteins and cellular proliferation contribute to maintaining healthy protein structures. By understanding the mechanisms involved in the maintenance or protein structures, it is hoped that these pathways can be targeted for the treatment of aging for extended healthspan.

Stable Isotope Approaches

The TRACD Laboratory specializes in the use of stable isotopic tracers for the measurement of metabolic flux and turnover. In particular, we helped pioneer the use of deuterium oxide (D2O) for the measurement of protein and DNA turnover in vitro and in vivo. Using this approach we have made important contributions to the areas of mitochondrial biogenesis, the maintenance of muscle mass, and the contribution of proteostasis to slowed aging. Along with our collaborators, we continue to develop new approaches and mathematical models to continue to advance this exciting technique.

Figure demonstrating the use of D2O for the measurement of protein and DNA synthesis. From: Miller, B. F., Drake, J. C., Naylor, B., Price, J. C., & Hamilton, K. L. (2014). The measurement of protein synthesis for assessing proteostasis in studies of slowed aging. Ageing Research Reviews. 18:106-11.

Canines as Models of Stress Resistance and Slowed Aging

Our work with collaborator Mike Davis has resulted in an increasing awareness about how rapidly dogs seem to adapt to stresses. Please see our recent publications for some of our research about bioenergetics in Alaskan Huskies:

Rapid adaptation to acute stresses, we and others hypothesize, should lead to better responses when faced with those stresses again later. Stress resistance seems to be a characteristic of increased lifespan and healthspan. Because it seems that dogs rapidly adapt to a variety of stresses, and because canine species—especially companion dogs—share the same environment with humans, dogs may be a very good model for understanding human aging. We have become involved in an NIH-funded effort to develop the domestic companion dog as a powerful model to better understand the biology of aging in humans. This effort is led by Dr. Daniel Promislow and others.