Diane C. Cabelof, Ph.D.
Assistant Professor
Wayne State University
The Aged Colon: Impact of Endogenous Damage and Proliferative Status on Chromosome Breakage
Colorectal cancer is the second leading cause of death from cancer, with nearly 150,000 new cases diagnosed each year. Dr. Cabelof will investigate whether age-related changes in DNA damage processing are responsible for the increased risk for colorectal cancer in the elderly. Through her studies, she aims to establish whether colorectal cancer risk in the elderly can be modified by dietary changes, and to establish a mechanism by which chromosomal damage arises spontaneously with age.
Sic Lung Chan, Ph.D.
Assistant Professor
University of Central Florida
A Novel Stress Response Ubiquitin-Domain Protein Counteracts Mutant A-synuclein Toxicity: A Therapeutic Target for Parkinson's disease
Prolonged or aggravated stress, caused by various pathophysiological conditions, to the endoplasmic reticulum (ER) - an essential intracellular organelle involved in maintaining intracellular calcium levels and protein folding - causes apoptosis (programmed cell death) and plays a role in neurodegenerative disorders such as Parkinson's disease. Neuronal loss in Parkinson's disease is often accompanied by the formation of protein inclusions composed of the A-synuclein protein that fails to fold properly. Accumulation of atypical proteins can inhibit the normal function of the ER. In an attempt to restore the function of the ER, the stressed neurons increase the expression of a selective group of proteins called ER stress proteins. Dr. Chan has identified a novel ER stress protein that protects neural cells against ER stress induced apoptosis. He will study the underlying mechanisms by which ER stress contributes to the development of PD, and by which this novel stress protein counteracts ER stress induced by protein inclusions. His results could help create new therapeutic strategies to counteract ER stress and combat neurodegenerative disorders.
Gregory David, Ph.D.
Assistant Professor
New York University School of Medicine
Function and Modulation of Chromatin Modifiers in Senescence and Aging
In the course of any individual’s life, each cell will undergo a limited number of divisions in a process called cellular senescence. This limitation – a normal biological process – prevents cells from uncontrollably and rapidly proliferating, which could result in numerous diseases such as cancer. The same process that protects against uncontrolled cell growth is also linked to cellular aging. Therefore, senescence and aging are intimately linked.
In every cell, DNA is wrapped around proteins named histones. It has been proposed that during senescence, DNA becomes associated more closely to histones, and therefore becomes less accessible to other proteins. This is the result of histone modifications, which are driven by enzymes that are called chromatin modifiers. Dr. David will investigate the function of specific chromatin modifiers in the establishment and maintenance of cellular senescence, as well as their role in aging. His research could provide a better understanding of the molecular basis for aging, and point to potential new approaches for targeted therapeutics for diseases of the bone marrow. Read more about cellular senescence on AFAR’s public education Web site, Infoaging, at http://websites.afar.org/site/PageServer?pagename=IA_b_sene_home.
Yuqing Dong, Ph.D.
Assistant Professor
Clemson University
Characterization of the Role of C. elegans Host Cell Factor (HCF-1) in Life Span Regulation Associated with DAF-16 and SIR-2.1
Genetic studies have revealed that the genes DAF-16 and SIR-2.1 are two major determinants of longevity. Dr. Dong has found that C. elegans host cell factor (CeHCF) is capable of regulating life span in the nematode C. elegans. Dr. Dong will investigate the molecular mechanism of life span regulation through the interplay of CeHCF/DAF-16/SIR-2.1 in C. elegans. The results from his research will greatly advance current understanding of the mechanism by which DAF-16 regulates the specific targets responding to certain environmental clues, and will help future researchers explore new longevity determinants. Dr. Dong's research will have important implications for the prevention and treatment of age-related diseases and disorders.
Peter Robin Hiesinger, Ph.D.
Assistant Professor
University of Texas Southwestern Medical Center at Dallas
Unsaturated Fatty Acid Regulation of Neurotransmission in Aging Neurons
Brain development, function, and aging are strongly influenced by lipid metabolism and intake. While the positive roles of unsaturated fatty acids like omega-3 and omega-6 are widely publicized, the molecular mechanisms by which unsaturated fatty acids affect the brain are mostly unknown. Dr. Hiesinger will test the hypothesis that increased production or dietary intake of specific fatty acids can positively influence neurotransmission in the aging brain. He will try to determine the molecular mechanism by which specific fatty acids improve brain function, and how this mechanism can be exploited to improve brain function during aging. His research may provide molecular insight into synaptic transmission in aging brain cells and yield a therapeutic approach for disorders that reduce synaptic function.
J. Kent Leach, Ph.D.
Assistant Professor
University of California, Davis
Age-Related Differences in the Osteogenic Potential of Adipose Derived Stem Cells
Cell-based therapies, in which fully mature bone-forming cells or precursor cells that possess bone-producing potential are delivered into a localized area of bone, have demonstrated the potential to heal large fractures or slow-healing bone defects. Most studies to date have examined the ability of cells from a young patient to heal fractures in a young patient, although the majority of non-healing fractures occur in the older population. Fat-derived stem cells are a promising cell source to promote bone healing, in part because of their ease of collection and potential to participate both directly and indirectly in the regeneration of bone. However, there is not a clear understanding of the differences between young and aged cells -- how bone-forming potential differs with age for fat-derived stem cells, whether fat-derived stem cells maintain their responsiveness to certain drugs which promote bone formation, and whether there are other potential targets for delivering drugs to aged cells that could be beneficial in bone healing. Dr. Leach will compare the ability of these young cells versus cells from older donors to form mineralized tissue. He will also characterize the mechanism of fat-derived stem cells to produce bone-like tissues by examining changes at the cellular and genetic level. The results of his study could potentially change the way bone fractures resulting from injury or bone loss are treated in the aged population.
Yilun Liu, Ph.D.
Assistant Professor
Yale University School of Medicine
Defining the Biochemical Functions of Rothmund-Thomson Syndrome Helicase RecQ4
The accumulation of DNA damage in our body is a major cause of aging. Our body has evolved a complex mechanism to ensure that this DNA damage, caused by radiation or chemicals, is efficiently repaired. Alterations in our DNA due to defective DNA repair machineries may result in cell death or cell transformation, leading to tumor formation and/or accelerated aging. Human RECQ family proteins are DNA repair proteins that are important for cancer prevention and the normal aging process. Mutations in one of the five human RECQ proteins, RECQ4, result in the Rothmund-Thomson Syndrome (RTS). RTS patients exhibit signs of premature aging, such as early development of cataracts and loss of hair. The goal of Dr. Liu's project is to understand the functions of RECQ4 and its role in normal development, and how mutations in RECQ4 contribute to premature aging. Overall, she hopes to gain a better understanding of how DNA damages and alterations contribute to the aging process and age-related diseases.
Ilhem Messaoudi, Ph.D.
Research Assistant Scientist
Oregon Health and Science University
Impact of Immune Senescence on Varicella Virus Infection, Latency and Reactivation in Aged Rhesus Macaques
Reactivation of the varicella zoster virus (VZV) when someone's immune system is weakened results in herpes zoster, more commonly known as shingles. There are an estimated one million new cases of shingles in the U.S. each year, and the majority of these cases occur in individuals over age 55. Vaccines to prevent shingles are only 50 percent effective. It is unclear which changes in older peoples' immune response are responsible for this increased susceptibility. Dr. Messaoudi has developed an animal model using rhesus macaques to characterize the immune response to the virus upon infection and reactivation. By comparing the varicella zoster induced immune responses in aged and juvenile nonhuman primates, she hopes to uncover the key immune deficiencies that allow VZV reactivation in older people. Her studies could ultimately create more effective vaccines against shingles.
Robert P. Rhoads, Ph.D.
Assistant Professor
University of Arizona
Impact of Endocrine-Related Changes with Aging on Satellite Cell-Induced Angiogenesis
Skeletal muscle loss due to aging is a major problem in the elderly. During aging, muscle mass diminishes, and the muscles have a reduced ability to repair. Muscle repair entails replacing damaged muscle fibers as well as repairing blood vessels and nerves. Prior research indicates that satellite cells - stem cells responsible for muscle fiber repair and growth - also have the ability to stimulate blood vessel growth (angiogenesis). The decrease in muscle repair during aging appears to be related to problems in satellite cell function. Research also shows that satellite cells are influenced by blood-borne (endocrine) factors. Dr. Rhoads will try to determine the role of endocrine factors in the regulation of satellite cells, and how those endocrine factors affect the ability of satellite cells to stimulate blood vessel growth in skeletal muscle. Improving the ability of aged satellite cells to repair muscle has the potential to reverse or halt skeletal muscle loss in elderly people. Dr. Rhoads's research could provide significant contributions to the design and development of strategies to improve skeletal muscle regeneration and lead to therapies aimed at preventing or slowing skeletal muscle loss in the geriatric population.
Michael F. Salvatore, Ph.D.
Assistant Professor
Louisiana State University Health Sciences Center
Role of Tyrosine Hydroxylase Phosphorylation in Age-Related Bradykinesia
Bradykinesia, a slowing of the execution of movement, affects nearly 30 percent of the elderly population by age 85 and is a cardinal sign of Parkinson's disease. However, there are currently no known treatments for non-Parkinson's bradykinesia, which studies show affects 10 percent of people age 65 and doubles in incidence every decade of life thereafter. Dr. Salvatore will study several molecules involved in the regulation of dopamine, an important neurotransmitter (messenger) in the brain. He aims to show that in aging, molecular deficiencies exist in dopamine neurons that are linked to age-related bradykinesia. His goal is to identify the age-related molecular differences that negatively and positively impact motor function in the elderly. This information could help with the development of drug therapies to treat elderly people with bradykinesia. His findings could also have significant overlap with findings from other research on how diet and exercise affect molecular events in the brain, which might enable prevention of bradykinesia.
James E. Thompson, M.D.
Research Assistant Professor
University of Pennsylvania
Murine Model of the Anemia of Aging and the Myelodysplastic Syndromes
About 10 percent of people age 65 and older have anemia (low red blood cell count). In up to one-third of these cases, the cause cannot be found. One possible cause of unexplained anemia with aging is a group of aging-related bone marrow diseases known as the myelodysplastic syndromes (MDS), which can lead to leukemia. Treatments for MDS, which evidence suggests is a mitochondrial disease of aging (mitochondria are the "powerhouse" of cells, providing most of the energy needed for normal functioning of cells), are limited because very little is known about the underlying cause. Using mouse models of mitrochondrial aging, Dr. Thompson will try to determine if the anemia of the mice is identical to that of human MDS, whether the anemia is due to mitochondrial changes in the bone marrow alone or if changes in other parts play a role, and whether the frequency of mitochondrial diseases of the marrow increase during human aging because of some advantage these changes give to bone marrow stem cells. Dr. Thompson ultimately hopes to determine how mitochondrial changes cause aging-related bone marrow disease. His research could be an important first step in learning how to prevent both unexplained anemia of aging and aging-related MDS.
Jian Yang, Ph.D.
Assistant Professor
University of South Alabama College of Medicine
A Novel Genetic Mouse Model of Chronic Activation of AMP-Activated Protein Kinase (AMPK) in Liver
Aging is often associated with increased fat mass and an increased risk of type 2 diabetes. Caloric restriction and the administration of resveratrol (a compound found in red wine) have been known to slow aging and extend lifespan by reducing fat mass and increasing insulin sensitivity (the body's responsiveness to insulin's action); at the same time increasing the activity of AMP-Activated Protein Kinase (AMPK) in the liver. AMPK is an important enzyme that governs energy metabolism and balance in mammals. It plays a key role in the regulation of glucose and lipid metabolism in the liver. Dr. Yang will study the role of AMPK in the aging process and age-related diseases in mammals using a novel genetic mouse model. If he finds that the activation of AMPK in the liver reduces age-associated obesity and the risk of type 2 diabetes, medicines that activate this enzyme in the liver could be developed to help improve human health and prolong life expectancy.
Yi Zuo, Ph.D.
Assistant Professor
University of California, Santa Cruz
Remodeling of Aging Neuromuscular Junctions Induced by Schwann Cells
The nervous system is made up of two classes of cells: neurons and glia. Schwann cells are the glial cells in the neuromuscular system. They play important roles in maintaining and modulating neuromuscular junctions (NMJs) - the sites where motor neurons contact muscle fibers - and are actively involved in repair processes following nerve injury. Working with fluorescent-labeled transgenic mice, Dr. Zuo will follow Schwann cell dynamics during the deterioration of aging NMJs. The disruption of structural integrity and decline in physiological function in aged NMJs are major causes for the reduction of physical performance and loss of independence in the elderly. Dr. Zuo seeks to understand the role of Schwann cells in the dramatic loss and changing of NMJs during the aging process. A better understanding of nerve-muscle-Schwann cell interactions will allow for more rational interventions in the aging neuromuscular system.
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Mark A. Eckert, Ph.D.
Assistant Professor
Medical University of South Carolina
Brain Imaging of Age-related Changes in Speech Recognition
The ability to follow conversation becomes more difficult as we get older. We may have difficulty hearing speech or maintaining focus on what people are talking about. Dr. Eckert's project uses brain imaging techniques to examine the structure and function of brain systems important for hearing speech (the temporal lobe cortex) and for maintaining focus on speech (the frontal lobe cortex). He will examine whether age-related declines in these systems can explain the speech recognition problems of older adults. Dr. Eckert's preliminary research suggests that older adults require more frontal lobe support to recognize speech in the easiest listening conditions, and that speech recognition problems may occur when frontal lobe attention systems can no longer compensate for age-related declines in brain volume or brain resources. His research may explain why some older adults do not benefit from hearing aids - declines in frontal lobe attention systems would limit their ability to focus on the speech that is amplified by their hearing aid. Frontal lobe attention systems are also engaged in other cognitive tasks, such as remembering facts, so declines in these systems could have wide-ranging effects on cognitive health.
Mauricio Rojas, M.D.
Assistant Professor
Emory University
Effects of Aged Extracellular Matrix on Stem Cell Differentiation
Stem cells are mobilized and recruited during lung injury as an endogenous mechanism to limit injury and promote repair. Localization of stem cells into the injured lung requires the interaction of the stem cells with proteins produced by lung cells. Age-associated changes on the protein composition can affect the number and quality of the stem cells that localize into the lung during injury. Dr. Rojas's study links senescence of the lung with inefficient stem cell recruitment. His main question is to determine if the alterations in the composition of the proteins of the lung during senesce would alters the stem cells capacity to localize into the injured lung. Preliminary results generated by Dr. Rojas' group, suggest that age-associated miscommunication between the lung and stem cells results in the recruitment of stem cells that promotes exaggerated repair and scarring associated with pulmonary dysfunction. The identification of the proteins that promote disrepair could result in the development of novel therapies for lung injury in elderly patients.
ROSALINDE AND ARTHUR GILBERT FOUNDATION/AFAR NEW INVESTIGATOR AWARDS IN ALZHEIMER'S DISEASE
Yaniv Assaf, Ph.D.
Lecturer
Tel Aviv University
Hippocampus Characterization of Mice Over-Expressing APP and APOE3/4 Using Multi-Dimensional MRI
Research summary to come.
Olivier Boutaud, Ph.D.
Research Assistant Professor
Vanderbilt University Medical Center
Quantification of the Relative Abundance of Secreted APP Alpha and Beta as a Biomarker of Alzheimer's disease
Present therapies for Alzheimer's disease treat symptoms, but do not change the clinical progression of the disease. Development of new therapies is hindered by a lack of reliable biomarkers of the disease's progression and of the effectiveness of the treatment. The products of digestion of the amyloid precursor protein (APP) by several enzymes are possible candidates for developing biomarkers. Two products of digestion are formed in a mutually exclusive way: the secreted APP alpha (sAPPΑ) and the secreted APP beta (sAPPΒ). Dr. Boutaud's research seeks to quantify whether relative levels of sAPPΑ and sAPPΒ could serve as an effective biomarker for Alzheimer's disease. This biomarker could potentially be used as a prognostic tool to track the progression of the disease and to monitor the biological effects of new therapies.
Chad Antony Dickey, Ph.D.
Assistant Professor
University of South Florida
The Role of Re-folding Chaperones in Tau Aggregation
Alzheimer's disease is the result of abnormal protein accumulation in the brain, with the primary risk factor being age. Dr. Dickey's goal is to identify ways in which these proteins accumulate, and to hopefully identify new drug targets for the treatment of Alzheimer's disease. Dr. Dickey intends to focus on the removal of the proteins once they have already started to accumulate by manipulating a class of proteins called molecular chaperones. These chaperones help in the processing of proteins within neurons and may represent an entirely novel class of candidates for therapeutic development in Alzheimer's research.
Isabella A. Graef, M.D.
Assistant Professor
Stanford University
Harnessing Endogenous Proteins to Prevent and Clear Pathogenic Protein Aggregates in Alzheimer's disease
Alzheimer's disease is characterized by the formation of abnormal protein clumps (aggregates). A protein fragment (peptide) called A-beta accumulates and forms aggregates in and around neurons, which initiates the cascade of events that eventually leads to the death of neurons and the development of Alzheimer's disease. One way to prevent and/or treat Alzheimer's disease would be to block early on the protein-protein interactions between the A-beta peptides, or to actively clear these aggregates before they cause neuronal damage. Dr. Graef has developed a novel strategy to design a small molecule that can attach itself to a chaperone, an abundant cellular protein that helps other proteins to fold properly. These new compounds can tether bulky chaperones to the beta-amyloid fragments and prevent them from forming large clumps. As a result, these molecules are effective at reducing protein clumping at concentrations 100 times lower than other blocking agents that have been tested. Through her research, Dr. Graef hopes to further develop this approach, contributing to the development of therapeutic agents that could prevent or delay the onset of Alzheimer's.
Indu Kheterpal, Ph.D.
Assistant Professor
Pennington Biomedical Research Center
Development of a Mass Spectrometric Screening Assay to Characterize Modifiers of A-beta Amyloid Aggregation in Alzheimer's disease
Dr. Kheterpal's research focuses on developing experimental tools to test and identify small molecules that slow, prevent, and/or reverse protein accumulation in Alzheimer's disease. The results have the potential to guide the creation of new medicines that will possibly cure and/or slow the progression of Alzheimer's disease. These new techniques may also be broadly applicable to more than 25 diseases, such as Parkinson's disease and type II diabetes, which are age-related and have been shown to be associated with protein aggregation.
Grace Elizabeth Stutzmann, Ph.D.
Assistant Professor
Rosalind Franklin University
Contributions of Early Calcium Signaling Dysregulations to Alzheimer's disease Pathogenesis
Dr. Stutzmann will examine how early disruptions in neuronal signaling pathways may later contribute to Alzheimer's disease pathology. Certain Alzheimer's disease-linked mutations are correlated with early increases in calcium levels within cells. Since calcium is a critical signaling factor in neurons, this disturbance may interfere with normal cellular function in the short term, and accelerate the pathological features of Alzheimer's disease in the long term. An important part of Dr. Stutzmann's study includes normalizing this atypical calcium to determine whether this reduces the later stage symptoms of Alzheimer's disease.
FANNIE E. RIPPEL FOUNDATION/AFAR NEW INVESTIGATOR AWARDS ON GENDER DIFFERENCES IN AGING
Jennifer S. Lee, M.D.
Assistant Professor
University of California, Davis
Endogenous Sex Hormone and Genetic Risk Factors for Stroke in a Biracial Cohort
As men and women get older, their risk of stroke increases significantly, especially among Blacks. Their production of estrogens and androgens (sex hormones) also change with age and differ by gender. Dr. Lee will investigate the relationship between the amounts of estrogen and androgen produced in older men and women and their subsequent risk of stroke, among Blacks and Caucasians. Her research may contribute to better identifying men and women at high risk for stroke, and lead to more beneficial hormone strategies to prevent and/or treat stroke in older men and women.
Rebecca C. Thurston, Ph.D.
Assistant Professor of Psychiatry and Epidemiology
University of Pittsburgh School of Medicine
Adiposity and Menopausal Hot Flashes Among Midlife Women
For many years, researchers and clinicians believed that heavier women had fewer menopausal hot flashes, in part because body fat secretes hormones such as estrogen that are used to treat hot flashes. However, the scientific community is now learning that heavier women seem to report more hot flashes. Dr. Thurston will use biological and self-report measures of hot flashes to evaluate the relationship between body fat and incidence of hot flashes. She will examine whether women with more body fat have more biologically-measured hot flashes, whether differences in reproductive hormones may explain any relations between body fat and hot flashes, and whether women with more body fat perceive and report their hot flashes differently than women with less body fat. Her research may inform new strategies - such as weight loss - for the management and treatment of hot flashes.
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