2012 Grantee Summaries

AFAR Research Grant Program

 

Anthony Cammarato, PhD
Assistant Professor of Medicine
Johns Hopkins University

Determining and manipulating age-dependent changes in myocardial stiffness, in vivo

A common characteristic of cardiac failure in old age is loss of elasticity that allows the heart to properly fill with blood in anticipation of its next contraction. Understanding the genetics behind age-related stiffening of heart muscle is the goal of Dr. Cammarato’s innovative research. Using live video and atomic force microscopy and fruit flies, he will perform the first direct analysis of age-associated mechanical changes in the hearts of living animals. With measurements of age-associated changes in heart muscle stiffness in hand, Dr. Cammarato will turn his attention to the genes that modulate the physiological properties of aging heart muscle. His hope is to identify potential targets for treating and possibly preventing the stiffening of heart muscle over time, thereby by mitigating one risk factor for heart failure.

 

Inactive older adults: determining the role of system A and L transporters underlying an amplified anabolic response in muscle

Regaining muscle strength after an extended period of inactivity requires both exercise and proper nourishment. When the elderly require long periods of bed rest due to illness or injury, they experience faster deterioration of muscle and longer periods of recovery.  In previous studies, Dr. Drummond has observed that the combination of age and inactivity can result in a significant drop in the effected muscles’ ability to process the essential amino acids (EAA) necessary to rebuild atrophied muscle. In this research project, Dr. Drummond will first test a 12-wk program of intense physical activity combined with nutritional supplements using enriched EAA. His goal will be to reverse atrophied muscles’ impaired responses to EAA intake. The data from this study will be used to design follow up experiments with the overarching goal of determining how to decrease muscle atrophy among the elderly when extended bed rest is required.

 

Christina E. Hugenschmidt, PhD
Instructor
Wake Forest School of Medicine

Differential relationships between diabetes risk factors and brain structure and function

The inability of our body’s naturally produced insulin to regulate blood sugar levels properly is a condition known as diabetes. Risk factors for Type 2 or adult-onset diabetes include obesity and aging. Diabetes increases both the rate of mild aging-related mental decline and the risk for dementia, including Alzheimer’s disease. However, not all people with diabetes or diabetes risk factors experience greater than normal mental decline. Dr. Hugenschmidt’s study will seek to determine the diabetes risk factors that most reliably predict greater risk of developing conditions like Alzheimer’s disease. Her team will add data on mental performance, brain structure and brain connectivity to existing data on reversing risk factors for diabetes from an ongoing weight-loss trial in older adults who were identified as at risk of developing diabetes. Understanding the biological mechanisms linking diabetes with dementia will help develop new and better treatment and prevention strategies.

 

 

Targeting CD137 to enhance RSV peptide vaccine efficacy in aged mice

Respiratory Syncytial Virus (RSV) causes about 12,000 deaths per year in the elderly. It is responsible for 11% of hospitalizations for pneumonia. Despite numerous efforts, no effective vaccine for RSV has been developed. Dr. Lee’s team found that impaired RSV-specific CD8 T cells and delayed RSV clearance in aged mice compared to young mice. Her team created a peptide vaccine approach called TriVax, which generated robust CD8 T cell response and complete protection against RSV infection in young mice but not in aged mice. Her current proposal will define whether co-administration with an agonistic antibody (CD137) may rescue TriVax efficacy to enhance CDB T cell response in aged mice. Her goals are to better understand the underlying mechanisms that lead to the decline of the immune system as we age and to establish a basis for a novel vaccine strategy against RSV in the elderly.

 

Multimodal neuroimaging biomarkers of caloric restriction protective effects in aging mice

Tests with a wide range of animals have shown that a diet restricting calorie intake while ensuring healthy nutrition slows the age-related decline of a variety of physiological functions. But the effect of caloric restriction (CR) on brain metabolism and cognitive function has not been widely studied. Dr. Lin proposes an innovative research model designed to document the effects of CR on the living brain. She will use non-invasive neuroimaging methods (e.g. MRI, PET) to confirm the protective effects of CR on brain metabolism as the brain ages and to explore the physiological effects on the brain’s mitochondria. This also will be the first study to investigate the correlation between memory and spatial information processing and the brain imaging results of her CR mice. Dr. Lin hopes her non-destructive research approach will help determine if CR is a viable approach to preserving the integrity of human brain function as we age.

 

 

Zinc homeostasis dysfunction in vascular aging

Cardiovascular diseases (CVD) are among the leading causes of death worldwide. Aging is associated with many physiological changes that can cause CVD. For example, increased inflammation in artery walls promotes atherosclerosis. This heightened inflammation response has been tied to changes in the function of aging vascular smooth muscle cells (VSMC). Dr. Salazar seeks a better understanding of the molecular mechanisms that lead to the breakdown of functions at the cellular level. In previous research, she has found that zinc deficiency is linked with an increased risk of CVD. How zinc levels contribute has not yet been explored. Dr. Salazar’s new research will use zinc-deficient and zinc-enhanced diets to test the effects on VSMC. The goal of her work is to provide insight to possible nutritional approaches to the lowering and/or treatment of age-related risk of CVD.

 

ERK5/KLF4 signaling and glia-neuron interaction

To date, most research on the causes of diseases characterized by the degeneration of neurons has focused on the breakdown of functions within the neurons. Much less research has been done on the various types of non-nerve pulse carrying brain cells called glia. Dr. Su’s work will focus on communication between neurons and glia. Research has already shown the steroid hormone progesterone can protect cells against agents that typically cause cell death. But that same protection is not as robust when neuron- or glia-enriched cultures are tested separately. This suggests that neuron-glia interaction may be involved in assuring the full beneficial effects of progesterone. Dr. Su’s work will focus on the signaling pathway between glia and neurons and its impact on progesterone-induced cell protection. This work could lead to novel strategies for preventing and/or treating neurodegenerative disorders associated with aging.

 

Determining neurogenesis-induced neural circuits in the aged mice

The brain’s plasticity to continuously generate and incorporate new brain cells into its circuitry, particularly in the hippocampus, plays a key role in our ability to think, learn, remember and express emotion. Creation of new brain cells declines as we age, leading to the mental deficiencies associated with growing older. Dr. Suh has developed a unique tracing system that allows his team to follow new circuit development in the adult hippocampus. His study will identify circuits in the brains of mice that support creation of new memory and learning ability, which seem to falter with age. His team will then test whether there is a difference in how these circuits perform in sedentary versus running mice. Dr. Suh’s study will provide a better understanding of the brain circuits that are disrupted as we age and provide insight to whether voluntary exercise may be a way to slow or even reverse aging-related loss of the circuit formation.

 

 

The role of mTOR in the development of cardiac hypertrophy during aging

Mammalian target of rapamycin, or mTOR, is an enzyme that regulates cell growth, movement and survival. Regulation of mTOR signaling has been shown to play an important role in the effects of aging at the cellular level. With 90% of all heart failure deaths occurring after age 70, Dr. Zhang is particularly interested in the role of mTOR on cardiac aging and the development of cardiovascular diseases (CVD). His preliminary studies have shown that mTOR signaling increases with age. He has also shown that suppressing mTOR signaling reduces the unhealthy enlargement of the ventricles of the heart, which is often characteristic of heart failure. With this new research, Dr. Zhang will further test his hypothesis that mTOR plays an important role in cardiac function over time by inhibiting mTOR signaling in his mouse model at different ages. His findings could lead to preventive therapies for CVD among the elderly.

 

AFAR Florida Research Grant Program

Mitochondrial isocitrate dehydrogenase and age-related hearing loss

Age-related hearing loss (AHL) is a common condition among people 65 years and older. Caloric restriction (CR), the reducing of food intake without malnutrition, has been shown to increase longevity and delay the progression of age-associated diseases, including AHL. CR is thought to slow the development of AHL by reducing the imbalance between the number of oxygen-containing molecules in the body and the body’s ability to regulate them, and/or by enhancing mitochondrial antioxidant defenses in the inner ear. Dr. Someya’s research to date has shown that CR slows AHL in part by increasing the activity of a specific mitochondrial enzyme that is critical to the ear’s biochemical defense mechanisms. The aim of this project is to determine whether this enzyme helps slow the progression of AHL in mice by enhancing the mitochondrial antioxidant defenses under CR conditions. The results of this project will provide an enhanced understanding of the fundamental molecular mechanisms underlying AHL.

 

New Investigator Awards in Alzheimer's Disease

 

Daniel Kaganovich, PhD
Assistant Professor of Cell and Developmental Biology
Hebrew University of Jerusalem

 

The cell biology of protein aggregation in a C. elegans Alzheimer Model

Our body has a highly specialized quality control system for balancing the production of amino acid chains, folding these chains into various functional proteins, and destroying misfolded proteins. If the system cannot fix or clear misfolded proteins, they tend to aggregate in cells to form structures called inclusion bodies. Alzheimer’s disease has a direct link to the failure of cells to properly manage protein folding. However, little is known about the role inclusions play in  aggregation toxicity. Dr. Kaganovich believes the starting point for uncovering the origins of AD pathology must be a thorough understanding of the general cell biological function of inclusions, and their potential role in modulating the toxic consequences of protein aggregation. His previous research has shed light on the possibility that aggregation and inclusions formation is not always toxic, and might sometimes be part of a natural protective process. His new study will move his research from an abstracted cell culture model into the roundworm (C. elegans) enabling him to explore the cell biology of protein aggregation in the context of a living, aging organism, and thereby provide insights to therapeutic targets when protein quality control begins to break down.

 

Glenn/AFAR Breakthroughs in Gerontology

 

INK-ER-Cre mice: a novel tool for uncovering how senescent cells cause age-related dysfunction

Senescent cells are old or damaged cells that have stopped dividing. Though they no longer behave like healthy cells, they continue to secrete proteins and enzymes into the body. Senescent cell secretions include proteins associated with inflammation in various tissues of the body. This inflammation is characteristic of many age-related diseases, such as dementia, depression, atherosclerosis, cancers and diabetes. Dr. Kirkland’s research on mice in collaboration with Drs. Baker, Tchkonia, van Deursen, and others at Mayo has already shown that removing senescent cells has a dramatic effect. It delays deterioration of muscle tissue and strength, slows the accumulation of fat under the skin and even wards of cataracts. Dr. Kirkland and his team will use a new mouse model to test their hypothesis that preventing the release of senescent cell secretions may delay or even prevent some age-related dysfunction. If successful, their research could lead to the development of therapies targeted specifically at senescent cell activity.

 

A novel protein disaggregase – from molecular mechanisms to novel cures

Alzheimer’s, Parkinson’s and Huntington’s are all examples of diseases characterized by the aggregation of proteins that would normally be removed by the body’s regulatory system. As they accumulate, these protein aggregates become toxic, choking off normal brain cell function. Understanding the molecular mechanisms of protein aggregation is critical to developing potential therapies. Molecular chaperones are proteins that assist in the creation of larger molecular structures without becoming part of those completed structures. Dr. Shan’s laboratory has discovered a novel molecular chaperone that reverses protein aggregation. Her team’s new research will uncover the molecular mechanisms by which this chaperone recognizes and disrupts protein aggregates. They will then engineer chaperones to remove protein aggregates associated with aging, thereby providing the foundation of a new approach to treating age-related protein aggregation.

Paul Beeson Career Development Awards in Aging Research

 

Pavan K. Auluck, MD, PhD
Research Fellow
Massachusetts General Hospital

Vesicle trafficking defects & mitochondrial dysfunction related to α-syn toxicity

Neurological disorders characterized by insoluble deposits of alpha-synuclein protein, such as Parkinson’s disease and dementia with Lewy bodies (DLB), are second only to Alzheimer’s disease in frequency of occurrence among the elderly. The causes of these diseases remain a mystery; however, genetic mutations and abnormal folding of α-synuclein are clearly part of the process. Dr. Auluck’s research will focus on two basic cellular functions that seem to be disrupted as a consequence of α-synuclein toxicity. First he’ll look at defects in the transporting of proteins between locations in the cell. He will then examine dysfunction in mitochondria that appears to be a consequence of a severe increase in accumulation α-synuclein and how these defects predispose affected brain cells to degeneration. His experiments will test the hypothesis that α-synuclein induced transport defects precede and cause mitochondrial dysfunction. The results will also deepen understanding of the basic cellular causes of α-synuclein associated diseases.

 

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S. Duke Han, PhD
Assistant Professor
Rush University Medical Center

Neural correlates of impaired financial and health-care decision-making in old age

Elderly adults are constantly faced with important decisions, such as financial and health-care issues. Recent studies suggest decision-making abilities can become significantly impaired with age. Relatively little is known about the correlation between brain measures and impaired decision-making in older adults. Dr. Han will apply his expertise in neuroimaging to a comprehensive, multi-disiciplinary study of non-demented older adults that will integrate multi-level imaging methods sensitive to brain structure and function. His work will also connect with recent approaches to studying how cognitive functions and memory combine with personality traits to form different styles of decision-making. The study and its findings will inform a comprehensive training program in neuroimaging, decision-making, bioethics, geriatrics, neuroepidemiology, biostatistics, and leadership skill development.

 

Amy Steves Kelley, MD
Assistant Professor
Mount Sinai School of Medicine

 

Improving care for older adults with serious illness

Advancing the quality and value of health care for seriously ill older adults is becoming an increasingly important social issue as the United States’ elderly population grows. Understanding what factors contribute to unnecessary or unwanted hospitalizations among older adults is essential for developing successful new models of care that focus on quality of life and patient satisfaction. Dr. Kelley’s study will evaluate factors, ranging from family support and health conditions to regional medical resources and patterns of care, that may influence treatment. She will then work with seriously ill people at risk of high-cost hospital-based care to identify “triggers” of unnecessary and/or undesirable hospitalizations and the barriers to avoiding them. She will learn from patients and families what factors lead to excess hospitalizations and how these barriers might be overcome. Her goals are to create a patient-centered approach that reduces unnecessary hospitalizations among seriously ill older adults and to translate the work into effective health care policies and clinical programs that better align treatments with patient preferences.

 

Geoffrey A. Kerchner, MD, PhD
Assistant Professor
Stanford University

 

Hippocampal structure and function in cognitive impairment

Though a great deal of research is being done on the causes and potential treatments of Alzheimer’s disease, Dr. Kerchner sees a critical need to identify biological indicators of AD at the earliest signs of memory loss. Such biomarkers could help with the timely delivery of disease-modifying therapies to minimally affected patients who have the greatest chance of curtailing the disease’s deadly progression. Neuroimaging holds great promise for identifying biomarkers, but conventional technologies are insensitive to early manifestations of the disease. Dr. Kerchner’s research will apply two complementary, high-resolution advanced imaging technologies to a study of the structural and functional changes in the hippocampus that correlate to memory loss. The ultimate goal of the study is to identify the baseline structural and functional imaging metrics that predict subsequent cognitive decline and may prove to be targets for proactive therapies.

Gerardo Moreno, MD, MSHS
Assistant Professor
University of California Los Angeles

Health IT decision support to improve medication management safety and quality

Patients dealing with multiple chronic health issues are frequently prescribed several medications. Managing multiple medications means dealing with issues related to drug interactions, inappropriate medications, and poor compliance with doctors’ prescribed use. These issues are further complicated among elderly patients who often have problems with memory and decision-making. Health information technology (HIT) holds great potential for improving the safety and quality of medication management. Dr. Moreno’s study in partnership with a rural community health center will examine medication practices among patients 60 and older. He will use feedback from physicians, nurses, pharmacists, and patients to help develop a prototype medication management application. His work will ensure any technology developed is widely accepted by the end-users and addresses the most important barriers to safe prescribing and compliance among older adults with chronic conditions.

 

Alexander Panda, MD, MPH
Brookdale Leadership in Aging Fellow
Yale University

 

Age associated defects in localization and trafficking of toll-like receptor 1

Dr. Panda’s research focuses on defects of the innate immunity arm in older adults. Aging is associated with a progressive decline in immune function (immunosenescence) resulting in increased susceptibility to viral and bacterial infections and decreased response to vaccines. Toll-like receptors (TLRs) are pattern recognition receptors that recognize conserved molecular patterns on microbes and are key to triggering antimicrobial host defense responses. Deficiencies in human TLR signaling lead to increased severity of several diseases, including sepsis, immunodeficiencies, atherosclerosis and asthma. Dendritic cells (DCs) are the major antigen presenting cells responsible for initiating an immune response. However, DC functions in aging have not been studied in detail. Dr. Panda recently demonstrated a generalized defect in TLR function in DCs from older individuals. As a Beeson Scholar he will study the mechanism of decreased TLR function in dendritic cells of older adults. His preliminary studies indicate a potential role of the chaperone Protein Associated with Toll-like receptor 4 (PRAT4A) in mediating the age-associated defects observed in TLR expression. He hypothesizes that the expression of PRAT4A is decreased with aging and therefore is a potential target for therapeutic intervention. In addition he will study underlying mechanisms of diminished PRAT4A and TLR1 expression in older adults. Ultimately, he hopes that his work will help explain the deterioration of immunity seen in older adults, and aid in the rational development of novel treatments and vaccines geared specifically towards older adults. “My research will benefit almost two million older adults hospitalized with an infectious disease each year in the United States.”

 

Steven J. Prior, PhD
Assistant Professor
University of Maryland School of Medicine

Effects of aerobic exercise on EPCs and vascular dysfunction in aging and T2DM

There is evidence to suggest that cardiovascular complications among the elderly and among people with adult-onset diabetes (Type 2) may in part be due to dysfunction in cells that are critical to the growth and repair of blood vessels. These cells, known as EPCs, appear to decrease in number and function in the circulatory system as we age and/or develop diabetes. Dr. Prior has done preliminary work that suggests aerobic exercise training may increase EPC and vascular function in diabetics, but that the positive effects of exercise may be reduced as we age. His new study will further test his hypotheses that reduced EPC function adversely affects vascular function in type 2 diabetics, and that there is an age-related difference in the ability of aerobic exercise programs to improve EPC function. The identification of the mechanisms and effects of EPC and vascular dysfunction could identify targets for therapeutic interventions to reduce risk for cardiovascular complications, especially in people over 65 years of age.

 

Alexander Smith, MD
Assistant Professor
University of California, San Francisco

 

Late life disability: epidemiology, symptoms, quality of life

The number of elderly people in the United States living with some form of disability will increase dramatically over the next several decades. Living with significant disability has major potential impacts on quality of life, caregiver burden, and the use of healthcare and social services. Little research has been done on how long elders with various disabilities can expect to live. This information is important from the perspectives of patients, caregivers, service providers and policymakers. Furthermore, quality of life concerns of elders with late life disability have not been well described. Dr. Smith’s  research will provide the first nationally representative estimates of the amount of time elders spend in disabled states prior to death, and examine how key demographic characteristics impact life expectancy. In addition, he will test and refine a conceptual model of quality of life for disabled elders and pilot a longitudinal study of factors influencing quality of life over time, including end-of-life outcomes.

Ellison Medical Foundation/AFAR Postdoctoral Fellows

 

 





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