Center Activities:
Dr. Roy G. Smith, HCOA Director, oversees the basic science laboratories of the Huffington Center on Aging which are involved in studies aimed at furthering our understanding of the molecular and cellular mechanisms of aging. Under Dr. Smith's leadership, HCOA investigators are studying the biochemical and genetic basis of limited cell proliferation that occurs in various cell types and organ systems during aging, including the aging skin, endocrine and cardiovascular systems. Their goal is to understand the changes that occur during aging, with the hope that they will be able to intervene in specific age related diseases and disorders to improve the quality of life of the elderly. Dr. Smith is aided by S. Robert Northrup, BA, Manager of Research Operations and Research Associate, is responsible for negotiating and purchasing scientific equipment, allocating space, enforcing safety policies and procedures, and designing experiments. He also leads scheduled tours of research laboratories, translating basic science studies into lay terms.

The laboratory of Gretchen Darlington, Ph.D. studies the age related changes in the expression of liver specific genes that control the response to inflammation. Older individuals have an altered response to infection and tissue damage. In addition, regeneration of the liver in the elderly is reduced and delayed. This may lead to an inability to respond to liver damage. The biochemical pathways of these biological processes and the genes that govern them are under investigation using cellular and mutational analyses.

The laboratory of Estela Medrano, Ph.D. is focused in elucidating mechanisms involved in protecting the skin against cancers in the elderly. The melanocytes are pigment cells that reside in the skin and other organs. They are responsible for the skin color, since they produce the pigment melanin, the amount and type of which is dictated by the genetic background of individuals and by exposure to ultraviolet radiation. Malignant melanomas, the most deadly of skin cancers, arise from melanocytes, and are still a genetic enigma. Presently we are undertaking two major research projects. One project involves the study of genes involved in chromatin remodeling and their possible role in aging and cancer of the melanocytes. The other project studies how the melanocyte regulates genes involved in human pigmentation. Knowledge from these projects will be used to design strategies to target specific oncogenes and to enhance the defense mechanism(s) of the skin against skin cancers.

Fred A. Pereira, Ph.D., Assistant Professor, Department of Otorhinolaryngology and Molecular and Cellular Biology, HCOA Core Faculty.  Dr. Pereira investigates the genetic and developmental regulation of the hearing and balance systems, which include the regulation of the development of the inner ear organ and the neuronal circuitry necessary to establish the complexities of hearing and balance. One area of focus is the analysis of a mouse mutant defective in the gene coding for the orphan nuclear receptor COUP-TFI. COUP-TFI mutants are profoundly deaf with a complete absence of auditory brainstem responses, which represent the relay of electrical stimuli from the inner ear through the brainstem. Indeed, COUP-TFI mutants have a foreshortened cochlear duct reducing the extent of frequency hearing and malformed vestibular chambers and lack of otoconia in the sacculus, which are critical for detecting vertical acceleration and result in balance deficits in early adulthood. Using gene chips and biochemical analyses they are interested in identifying and understanding the molecular signaling pathways regulated by genes such as COUP-TFI to provide insight into understanding human disorders of auditory and vestibular function, and congenital and age-related hearing and balance disabilities.

George E. Taffet, M.D. conducts studies of aging and aging-related diseases of the cardiovascular system. His approach combines basic science and clinical investigation and focuses on factors leading to diminished work capacity in healthy older people and investigation into the prevention and treatment of disability arising from heart failure. Normal aging is accompanied by an impaired ability of the heart to relax and refill. This diastolic dysfunction is one of the limits of exercise tolerance in older people and predisposes them to heart failure. Dr. Taffet showed that a protein important in cardiac relaxation is decreased in the old rat heart. He and Dr. Charlotte Tate, demonstrated that exercise would improve this aspect of heart function in part by increasing the content of this protein. Subsequently, they have found that caloric restriction also prevented age related diastolic function in rodents. The group's present endeavors include exploring other ways to improve cardiac relaxation and evaluating cardiovascular function in old and transgenic mice.

Nikolai A. Timchenko, PhD, Associate Professor, Department of Pathology: HCOA core faculty.   Dr. Timchenko’s research is focused on the investigations of a molecular basis for the loss of proliferative response in livers of old animals. He showed that a liver specific transcription factor C/EBPa causes growth arrest in young livers via a direct inhibition of cyclin dependent kinases 2 and 4.  Aging switches C/EBPa growth arrest from the inhibition of cdks to repression of E2F transcription. Old livers contain high levels of C/EBPa and are not able to induce E2F target genes in response to partial hepatectomy.  The failure to activate E2F targets leads to the reduced and delayed proliferative response in old livers. Timchenko’s lab is investigating the molecular mechanisms responsible for the age-associated switch of C/EBPa from cdks to E2F complexes.  A second direction in Dr. Timchenko’s laboratory is the study of the role of RNA binding proteins in the development of a senescent phenotype in human fibroblasts. These studies demonstrate that aging affects activity of certain RNA binding proteins leading to alterations in translational machinery and to cellular senescence.  The lab is investigating the age-dependent mechanisms that regulate activities of RNA binding proteins.

Xiangwei Wu, PhD, Assistant Professor, Department of Molecular and Cellular Biology; HCOA Core Faculty. The research projects in Dr. Xiangwei Wu's laboratory are designed to elucidate the function of
the tumor suppressor p53 in cell cycle checkpoint control and identification of factors involved in this process. One area of investigation focuses on the post-translational modification of p53, including phosphorylation and acetylation, and how this may affect ubiquitination and degradation, an essential determinant in p53¹s ability to mediate its function. To address how p53 induces cell death by apoptosis,a new putative zinc finger transcription factor Pw1/Peg3 was identified that acts as a potential mediator in p53-dependent apoptosis. The focus of the research is on how p53 and Pw1/Peg3 induce changes in the mitochondria as a critical step in p53-mediated cell death pathway. 

Hui Zheng, PhD, Assistant Professor, Department of Molecular and Human Genetics; HCOA Core Faculty. Dr. Zheng's research focuses on identifying targets that can be exploited for the prevention and treatment of Alzheimer' s disease (AD). AD is a neurodegenerative disorder associated with cognitive impairment and memory loss. It is the most common cause of dementia in the elderly. Dr. Zheng's laboratory is identifying and characterizing AD related genes and pathways in vivo using transgenic and gene knockout technologies. Three genes have been identified that are genetically linked to AD. These are the amyloid precursor protein (APP) and presenilins (PS1 and PS2). Mutations in these genes lead to early onset of Alzheimer's disease. Dr. Zheng's laboratory created knockout mice that are deficient in APP or PS1, as well as transgenic mice expressing human APP or PS1 containing mutations that are associated with early onset AD. APP knockout mice are viable but exhibit learning and memory defects. Deletion of PS1 in mice results in embryonic or newborn death, a phenotype that can be rescued by neuronal expression of human PS1. APP transgenic mice develop AD pathology, which is accelerated by PS1 mutations. Analysis of the mice has provided important information regarding the physiological functions of APP and PS1 as well as the pathological mechanisms of disease-causing mutations. Dr. Zheng continues to use mouse genetic approaches to seek further understanding of AD pathogenesis in vivo. This understanding will be critically important for the prevention and treatment of this devastating disease of aging.

NIA-Program Project Grant
An NIA-Program Project Grant formerly led by Dr. James Smith is a collaborative effort between five individual laboratories using various model systems of cellular senescence: normal human fibroblasts, adrenocortical cells, hepatocytes and melanocytes and various immortal human cells lines. This team works together on similar goals, using common techniques and approaches to answer questions regarding the molecular and cellular mechanisms involved in senescence and immortalization. These studies will examine the changes in gene expression that occur in cells as they age in vitro and in vivo, and will establish the differences and similarities in the pathways that lead to inhibition of cell proliferation, and to eventually understand the basic molecular mechanisms involved in human cellular senescence and the reverse phenomenon of immortalization. The scientists involved in this program project include: Gretchen Darlington, Ph.D., Nikolai Timchenko, Ph.D.,  Estela Medrano, Ph.D., James Smith, Ph.D., Olivia Pereira- Smith, Ph.D., and Peter Hornsby, Ph.D., at UT Health Science Center, San Antonio

Ethics Research Team
The HCOA Ethics Research Team includes Dr. Larry McCullough and Nancy Wilson, LMSW. This team is a founding component of a larger multi-departmental collaborative effort at Baylor addressing ethical and health care utilization issues. Areas of investigation addressed by the team involve ethical dilemmas, personal values, and decision making; issues surrounding life-sustaining technology; and health care utilization and quality of care. Specific efforts initiated by the team include projects designed to implement and test: a) the effectiveness of increased expression of values in long term care decision making, b) measurement of potential enhancement to well-being with increased patient autonomy, and c) mechanisms to increase the frequency of advanced directive discussions.