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South Texas Veterans Health Care System (STVHCS)

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GRECC Research

Al Fisher, MD, PhD

Led by Alfred Fisher, MD, PhD, Associate Director for Research, the San Antonio GRECC has an active research program devoted to developing newer and better ways to improve the health and quality-of-life of older Veterans. Our research is focused on gaining a better understanding of the basic mechanisms of aging, as well as the pathophysiology of metabolic and inflammatory conditions that affect the lives of millions of aging Veterans.

Our current research focus is centered on two broad themes: Metabolism and Inflammation. Individual projects focus on diabetes, diabetic nephropathy, nonalcoholic liver disease, frailty, sarcopenia, Alzheimer‘s disease, Lewy body disease, ALS, Parkinson‘s disease, cancer, and salivary hypofunction. The projects described below are currently underway and aimed at understanding the basic biology of aging, the mechanisms regulating longevity, and the pathophysiology of age-related diseases.

Dr. Fisher's expertise is in clinical Geriatrics and the use of the nematode, Caenorhabditis elegans in aging research. He is particularly interested in the roles of metabolism in the aging process. Specific projects in the lab include: (1) examining how metabolic stress alters proteasomal function and expression, (2) exploring how mitochondrial function changes during aging via non-invasive techniques, (3) determining how amino acids can impair insulin-like signaling, and (4) testing whether oxidative stress responses are controlled by both cell autonomous and non-autonomous mechanisms.

Current Research Projects

  • Diabetes, Obesity, and Molecular Effects of Exercise: Drs. Nicolas Musi has several ongoing projects focused on the cellular and molecular basis for age-related changes in glucose and lipid metabolism and the pathogenesis of insulin resistance and sarcopenia in aging and diabetes. These studies investigate how mitochondrial dysfunction, oxidative stress, and inflammation are involved in age-related alterations in glucose and lipid metabolism. Studies in Dr. Amrita Kamat’s laboratory focus on how excessive accumulation of fat in the liver impairs its function and is associated with the development of various components of the metabolic syndrome including non-alcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus and cardiovascular diseases.
  • Sarcopenia and Frailty: The loss of muscle mass that occurs during aging often leads to disability, decreased physical activity, and loss of independence. Sarcopenia also contributes to the pathogenesis of age-related diseases, such as diabetes. Ongoing studies in Drs Musi's laboratory investigate the role of increased oxidative stress and IKK/NFkB signaling in the pathogenesis of sarcopenia. Dr. Sara Espinoza is studying the pathophysiology of frailty using a comparative proteomic analysis of plasma glycoproteins. Finally, Dr. Dean Kellogg is studying how increased oxidative stress in aging has been implicated as a major factor in age associated impairments in both reflex and local skin vascular control mechanisms.
  • Insulin/mTOR Signaling (Longevity Studies): The only manipulations currently shown to retard aging in mammals are caloric restriction and genetic mutation of the insulin and insulin growth factor (IGF)1 signaling pathway. However, these manipulations cannot be translated easily to humans. Thus, several ongoing projects in the laboratories of Drs. Randy Strong and Elizabeth Fernandez focus on the life extending effects of rapamycin.
  • Inflammation and Neurodegenerative Disease: Inflammatory processes have been implicated in neurodegenerative disorders, such as Alzheimer‘s disease and Lewy body disease. The latter is particularly common among Veteran patients. Dr. Donald Royall has developed a research program largely directed toward improving the psychometric assessment of dementing illnesses. He is currently developing latent variables, derived from longitudinal as well as cross sectional data that can be used in the search for dementia-related biomarkers. Drs. Randy Strong and Elizabeth Fernandez are conducting studies in mice with reduced levels of Aldh1a1 and Gpx1 expression under conditions in which mitochondrial complex I is impaired, to determine if this will lead to the amplification and accumulation of reactive species and highly reactive biogenic aldehydes.
  • Inflammation and Oral/Periodontal Disease: In an ongoing research collaboration with Rice University and Dr. Spencer Redding (Chair, Comprehensive Dentistry, UT Health Science Center), Dr. Chih-ko Yeh is developing a Lab-on-a-Chip multiplex diagnostic for acute myocardial infarction using saliva samples in pre-hospital settings (e.g., in ambulance) and for other diseases (e.g., oral and systemic cancers).
  • Regenerative Medicine: Many individuals, especially Veterans, may benefit from the application of regenerative medicine to the therapy of human disease. In the future, regenerative medicine may offer better regeneration of organs that have suffered damage from trauma or other events, and better approaches to the therapy of degenerative diseases that impair function and shorten life in older individuals. An important discovery for regenerative medicine is induced pluripotent stem (iPS) cells. iPS cells are like embryonic stem cells, yet can be derived from any adult cell, such as a skin cell. Studies in Dr. Peter Hornsby's lab are aimed at testing the concept that when iPS cells are derived from the skin cells of a individual patient, they should be able to be transplanted back to the same patient without rejection. Before this is applied to human patients, the properties of iPS cells must be thoroughly explored in suitable animal models, to make sure that autologous cell therapy is both safe and effective. For this purpose nonhuman primates are ideal, because of their relatedness to humans and their similar central nervous systems.

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