Hani Atamna, PhD
Assistant Professor
The Commonwealth Medical College
The Anti-Aging Activity of Methylene Blue
Based on previous studies, Dr. Atamna has found that methylene blue (MB) delays cellular senescence by improving the metabolic activity of the mitochondria, the powerhouses of the cell. Dr. Atamna found that MB restores the decline in memory and muscle strength in old mice fed methylene blue. MB, used for decades to treat various ailments and also to stain tissue, has no known side effects. Dr. Atamna hopes to understand how it works to improve memory and muscle strength in humans. "MB has the potential to treat or delay the onset of Alzheimer's disease," Dr. Atamna said. "This research will justify clinical use to specifically target and cure Alzheimer's disease."
Ratan K. Banik, PhD
Assistant Professor
New Jersey Neuroscience Institute
Effects of Age on the Chemosensitivity of Cutaneous Pain-Sensing Afferents
About 40 percent of patients over 65 report little or no pain associated with inflammation, post-surgery and cancer. "Although this might sound like a blessing of age, in fact clinical reports show that an elderly patient is in imminent danger since the 'warning system' of her body is not working," Dr. Banik said. Many diseases are associated with the release of chemicals around nerve endings in the skin. It is not known if the nerve endings lose their sensitivity to these chemicals as a result of age. The goal, then, is to determine whether there is any age-related change in the function of pain-sensing neurons in the skin. This will be done by recording the activities of single pain-sensing neurons in response to a cocktail of chemicals. If this turns out to be the case, doctors may be able to "predict a greater level of underlying pathology when elderly people report of pain," Dr. Banik said.
Liang Chen, PhD
Assistant Professor
University of Southern California
Statistical Methods for Genetical Transcriptome Studies of Aging
Aging is one of the most complicated biological processes that might involve thousands of genetic and non-genetic components. "There is great interest to clarify to what extent lifespan variation can be attributed to genetic variation," Dr. Chen said. This research aims to develop statistical and computational ways to identify genetic loci related to aging and determine how these loci control other "downstream" genes and biological pathways. Understanding the mechanism of aging "will shed light on prognosis and treatment of aging-related disabilities and diseases," Dr. Chen said.
Julie Dumas, PhD
Research Assistant Professor
University of Vermont
Estrogen Attenuation of Cholinergic-Induced Alterations in Fronto-Parietal Brain Activation during Working Memory in Older Women
Studies have suggested that changes in mental abilities as we age may be the result of chemical changes in the brain. The loss of estrogen after menopause may accelerate this change in women. Dr. Dumas is looking at whether giving the hormone estrogen will affect the system in the brain that uses acetylcholine, a naturally occurring chemical associated with attention and memory. She will first administer estrogen to postmenopausal women ages 50-65. She then will give cholinergic medications that temporarily affect the ability to perform a working memory task. She will then use functional MRI to assess how estrogen changes the negative effects of the cholinergic drugs. "As women continue to take estrogen for management of menopausal symptoms, it is important to understand the neurobiology underlying the estrogen effect on cognition," she said.
David Gallo, PhD
Assistant Professor
University of Chicago
Neurocognitive Effects of Aging on Memory Retrieval Processes
Memory for perceptually detailed events, such as pictures, is better in aging than memory for less detailed events, such as verbal information. Detailed memories may rely on posterior regions of the brain that are relatively unaffected by aging, compared with more frontal regions. To test this, Dr. Gallo will use functional MRI to compare brain activity during memory retrieval in younger and older adults. "By understanding the neural systems that contribute to memory and how they are or are not affected by normal aging, we will be in a better position to diagnose and treat age-related diseases," he said.
Angela Gutchess, PhD
Assistant Professor
Brandeis University
Compensatory Changes in Neural Recruitment with Age
Memory and other cognition functions decline as we age. But measures of brain activity do not reflect a simple pattern of loss with age. Rather, Dr. Gutchess said, "functional MRI reveals flexibility in the neural response and even compensation: Older adults recruit additional regions of the brain that are not used by young adults for the same tasks." Using functional MRI, her study will examine young and old adults to look at how the prefrontal cortex responds differently with age and how older adults recruit the region in response to age-related changes in vision or memory. "Understanding the conditions under which older adults recruit additional neural resources will allow us to better understand the avenues available for compensation," she said.
Ji Li, PhD
Assistant Professor
University of Wyoming
Alterations in AMP-activated Protein Kinase (AMPK) Signaling Pathway in Response to Ischemia with Aging
Our heart functions less well and is more susceptible to damage as we age. But there is little evidence linking a decline in tolerance to ischemic stress to changes in specific stress signaling pathways. Dr. Li has found that one pathway, the AMP-activated protein kinase (AMPK) signaling pathway, plays an important role in limiting cardiac cell death during heart attack and stroke. Dr. Li believes that aging is associated with a decline in the ability of cardiac cells to activate AMPK and hopes to clarify its role in impaired ischemic tolerance. This could lead, he said, to understanding whether changing behavior, such as exercise and diet, leads to AMPK activation and could limit damage to the heart.
Xiongbin Lu, PhD
Assistant Professor
University of South Carolina
Protein Phosphatases in the Regulation of ATM-p53 Signaling Pathway and Cell Senescence
Cell aging is triggered by internal and external DNA damage stresses. These stresses initiate the ATM-p53 response pathway that eventually leads to cell senescence. Many studies have been done on the activation of the ATM-p53 pathway but little is known about how this pathway is shut off. Previous studies have found that Wip1 phosphatase(wildtype p53 induced phosphatase 1, or PPM1D) inhibits the ATM-p53 pathway. Dr. Lu hopes to understand exactly how Wip1 regulates the pathway in aging human cells. "Our research will help us and other researchers better understand molecular mechanisms in aging and age-related disorders," Dr. Lu said.
Sarah Milton, PhD
Assistant Professor
Florida Atlantic University
Methionine Sulfoxide Reductase A and Resistance to Oxidative Damage in
an Animal Model of Aging without Senescence
Research suggests that free radicals from aerobic cellular respiration causes oxidative damage to proteins, lipids and DNA. The buildup of this damage has been implicated in a range of age-related diseases, from stroke, to ALS, to Alzheimer's disease and to cataracts. The peptide Methionine sulfoxide reductase is a "repair enzyme" for oxidatively damaged proteins and amino acids. The freshwater turtle is the only known vertebrate animal in which the enzyme is regulated in response to changing oxygen levels. This makes this turtle "a unique model in which to examine the regulation and function of a compound that appears to be critically important in staving off age-related diseases," Dr. Milton said.
Michael Oertel, Ph.D.
Assistant Professor
Albert Einstein College of Medicine
Role of Aging in the Mechanism of Liver Repopulation by Transplanted Fetal Liver Stem/Progenitor Cells
More than 30,000 people die each year of chronic liver disease. A liver transplant is the only treatment. But because of a severe organ shortage researchers are trying to find alternatives, such as replacing diseased liver tissue by stem cell transplantation. Dr. Oertel and colleagues have shown that fetal liver stem cells can grow in a normal liver in rats. What's more, the growth is dramatically greater in older rats compared with younger rats. Now he is trying to understand why this is so. "If the findings in our studies are applicable to humans, they will have tremendous clinical implications for developing cell therapy strategies," Dr. Oertel said.
Carlos Orihuela, PhD
Assistant Professor
University of Texas Health Science Center in San Antonio
Age-Dependent Toll-Like Receptor Dysfunction Increases Susceptibility to Pneumonia
Toll-like receptors (TLR) are proteins on the surface of cells that recognize microorganisms during an infection and start the cell-signaling processes that activate the immune system. Aging is associated with an age-related decline in the immune response and increased susceptibility to pneumonia. Dr. Orihuela and his colleagues hypothesize that dysfunctional toll-like receptors in the lungs contributes towards the susceptibility of the elderly to pneumonia. To test this, he will measure the amount of TLRs in the lungs of young, mature and aged mice and determine the ability of aged TLRs to convey a signal to the cell. "Findings identified will help us to understand why the elderly are more susceptible to pneumonia and may serve as the basis for preventive medicine and/or improved pharmacological intervention," he said.
William Schrage, PhD
Assistant Professor
University of Wisconsin
Aging and the Red Blood Cell: Linking Endothelial and Exercise Dysfunction
In order to regulate blood pressure, our bodies must tightly control blood flow to the muscles. Red blood cells release a substance called ATP, which may precisely match blood flow to where oxygen is needed most. But almost nothing is known about how ATP is released in the blood from red blood cells or how its release changes blood flow. By having older and younger adults exercise and then measuring their ATP, Dr. Schrage hopes to see whether ATP is an important signal that will control blood flow and whether this signaling is impaired in older people. "If we can understand what is going wrong with ATP release from red blood cells, other scientists can develop specific signals for improving ATP signals," he said. This may in turn help older adults tolerate exercise and activity better.
Susmit Suvas, PhD
Assistant Professor
Oakland University
Role of Programmed Death Receptor-1 on Aging CD4+ T cells
Influenza has more impact on people over 65, largely because of defects in their immune cell types. Understanding the causes of these defects "might lead to the development of new strategies to enhance vaccine efficacy" in the elderly, Dr. Suvas said. Preliminary research shows a dramatic increase in the proportion of programmed death receptor-1 (PD-1) molecule expressing CD4+ T cells in uninfected aged mice. He hypothesizes that PD-1 expression on old CD4+ T cells makes them dysfunctional in aged animals.
ROSALINDE AND ARTHUR GILBERT FOUNDATION/AFAR NEW INVESTIGATOR AWARDS IN ALZHEIMER'S DISEASE
Christopher Conrad, PhD
Assistant Professor
Columbia University
RNAi and Genetic Linkage of AD
Current methods for discovering genes associated with Alzheimer's
disease often require years of verification. Dr. Conrad hopes that by
using cellular models, he can come up with a way to more quickly
identify promising genes for further, in-depth study. He is focusing on
31 genes, all expressed in the brain, in a recently identified region on
chromosome 3, 3q28, which is associated with late onset Alzheimer's
disease. By eliminating each gene, he can see what impact that has on
cellular models of Alzheimer's disease. "Our project will investigate
whether our method will accelerate the identification of Alzheimer's
disease-associated genes," he said.
Koichi Iijima, PhD
Assistant Professor
Thomas Jefferson University
The Role of Histone Modifications in Alzheimer's Amyloid-Beta42-induced Neurotoxicity inVivo
Abnormal accumulation of a peptide composed of 42 amino acids, called amyloid-beta, in the brain is suspected of playing a central role in the development of Alzheimer's disease. However, it remains unclear how amyloid-beta causes dysfunction and degeneration. De-acetylated histone proteins tightly package DNA. Regions of tightly packaged DNA are called heterochromatin; there is limited transcription of genes in these areas. In Alzheimer-affected brains, heterochromatin formation is increased. But, Dr. Iijima said, it is "not understood whether these changes are a cause or a mere consequence" of the disease. Using a genetically altered fruit fly carrying human amyloid-beta, Dr. Iijima found that histone acetylation levels were reduced in the fly brains. In addition, inhibiting the function of histone acetyltransferase (HDAC) complex appeared to protect against amyloid-beta induced dysfunction. The study "may encourage the exploration in the application of inhibitors of HDAC complex as a potential therapy" for Alzheimer's disease," Dr. Iijima said.
Suman Jayadev, MD
Acting Assistant Professor
University of Washington
Presenilin-2 Mutations and Microglia Function in Alzheimer's Disease
Inflammation in the brain has been implicated in the development of Alzheimer's disease. Dr. Jayadev hopes to understand how this inflammation causes or worsens degeneration in Alzheimer's disease by introducing Presenilin-2 mutations into brain immune cells, or microglia. Her goal is to understand how Presenilin-2 may contribute to that degeneration. Presenilin-2 mutations have been shown to cause familial Alzheimer's disease. She then will assess the impact of these mutations on the normal functions of the microglia. "Characterizing this novel role for presenilin and describing its function and dysfunction may reveal additional and perhaps more specific targets for drug therapies," Dr. Jayadev said.
Ling Qi, PhD
Assistant Professor
Cornell University
Manipulation of Unfolded Protein Response in Neurodegeneration
Both Alzheimer's and Parkinson's diseases share a common pathology: accumulation of insoluble, misfolded protein deposits. Dr. Qi's research focuses at the genetic level on defense mechanisms in the brain that might prevent the accumulation of those deposits, also known as unfolded protein response (UPR). Specifically, he is looking at whether enzymes, histone acetylases CBP/P300, can activate a key protein in UPR, XBP1. XBP1 is known to control many components of protein folding and degradation. Thus, it may be capable of preventing the accumulation of protein aggregates and, ultimately, the death of neurons. This one day could lead to gene therapy, he said. "Genetic regulation is very complex," he said. "This is the very first step to understand the transcription event occurring during UPR. It can lead to future investigations so that we may get closer and closer to understanding these diseases."
Inna Slutsky, PhD
Lecturer
Tel Aviv University
Initiation of Alzheimer's Disease: From Inhibition of Neprilysin Activity to Temporal Code at Individual Hippocampal Synapses
A loss with age of neprilysin, an enzyme participating in the clearance of beta amyloid peptides in the brain, has been proposed to cause the cognitive impairments in common, late-onset Alzheimer's disease. "The mechanisms transforming neprilysin deficiency to synapse loss... in AD subjects remain obscure," she said. Synapse loss is the most obvious physical sign of memory loss in Alzheimer patients. Dr. Slutsky hopes to determine how neuronal activity regulates neprilysin expression, release of beta amyloid peptides and the number of functional synapses in physiological and pathological conditions. She will use high-resolution optical imaging that can look at individual synapses in hippocampal neurons and electrophysiology that can monitor neuronal connections. "Understanding the physiological functions of neprilysin and amyloid beta peptides is crucial for targeting the early synaptic dysfunctions to prevent synapse loss and memory decline in AD," she said.
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