2009 (to date)

Peter M. Broglie - North Carolina State University - GSK Award

Alzheimer’s disease is one of many aging-associated diseases and the most common neurodegenerative disease. In Alzheimer’s disease patients, Amyloid β (Aβ), an inappropriate cleavage product of the amyloid precursor protein, that when accumulated within a neuron leads to neuronal cell death. Aβ induces misfolded proteins, stress conditions including inflammation, and impairment of the mitochondria. Such stress conditions normally induce autophagy, which is a biological process to protect cells from stress conditions by removing misfolded proteins and dysfunctional organelles. Impaired autophagic process is associated with Aβ pathology. For example, beclin 1, an essential mediator of autophagy, is found to be reduced in the brains of Alzheimer’s patients. Therefore, it is anticipated that upregulation of autophagy improves Alzheimer’s disease conditions. However, the regulatory mechanism of autophagy still remains largely elusive. We have recently found that TAK1 (TGF-β activated kinase 1) binding protein, TAB2, binds to beclin 1. Furthermore, we found that TAB2 is essential for preventing inflammatory cytokine tumor necrosis factor (TNF)-induced cell death. Based on these results, we hypothesize that TAB2 forms a complex with beclin 1 in response to stress in neurons and this complex may be essential for inducing autophagy resulting in cell death. We propose to delineate the roles of TAB2 in autophagy and in Alzheimer’s disease pathogenesis, which could lead a novel pharmaceutical target for Alzheimer’s treatment.

Arati Inamdar - Honorary Irwin Rose Awardee - University of Alabama

In addition to genetic causes, environmental factors are proposed to contribute to the sporadic forms of Parkinson’s disease (PD). Among the various candidate environmental factors, recent concern has been raised regarding exposure to the soil-bacteria, Actinomycetes in agricultural populations, who are known to exhibit an increase in the incidence of PD. Our collaborators in The Caldwell Lab (University of Alabama), recently discovered that exposure to crude conditioned medium of Streptomyces venezuaelae, species belonging to Actinomycetes group, causes the loss of dopaminergic (DA) neurons of C. elegans. However, the mechanism through which such medium of S. venezuaelae causes loss of DA neurons is not known. We have recently found the induction of nitric oxide and the activation of nitric oxide synthase (NOS)-expressing cells around the DA neurons in adult fly-brain in response to paraquat exposure, a well-known herbicide used to generate PD symptoms in PD models. Therefore, I hypothesize that exposure to crude conditioned medium of S. venezuaelae induces PD symptoms in Drosophila along with activation of NOS, a major component/marker in neuron death. Therefore, my research proposed to elucidate the mechanism(s) through which crude conditioned medium of S. venezuaelae induces PD symptoms, which could be targeted to prevent or delay PD progression in the aging and agricultural population.

Benjamin Parrott - University of Georgia

Adult stem cells are responsible for maintaining certain tissues for the life of an organism. Recent studies have demonstrated that the self-renewal and replenishing abilities of these stem cells are drastically reduced with increases in age (Boyle, et al. 2007). To understand how aging compromises these abilities, we must discover the basic genetic and molecular pathways that govern the balance of self-renewal and differentiation. Seven-up is a member of the orphan nuclear/steroid receptor family in Drosophilia, and is 93% identical to its human homologue, COUP-TF. It has been demonstrated that seven-up plays a key role in hormone signaling and thus represents an attractive link to the age-related decline observed in cellular populations arising from adult stem cells. My research seeks to discover principles that govern interactions between adult stem cells and their non-stem cell counterparts. These interactions are required for the maintenance of stem cells and their differentiating daughters, including properties that are negatively affected by age. Thus, identifying and characterizing genetic pathways responsible for these interactions will provide specific networks that can be probed for age-associated changes.

2008

Laura Bonafacio - UNC Chapel Hill - GSK Award

Aging, despite being a fundamental process of all human life, is a complex amalgam of both environmental and genetic mechanisms that has evaded complete understanding.  miRNAs (small, non-coding RNAs that regulate the expression of target mRNAs) are known to impact both development and lifespan (in some species), but a role for miRNAs in aging has yet to be defined.  My research focuses on elucidating the role of miRNA in aging and age-related diseases.  This knowledge should help advance our understanding of age-related diseases and facilitate the design of new treatments for these diseases.

Mirnella Byku - St. Louis University

Neuropeptide Y (NPY) is a cotransmitter with Norepinephrine (NE) and Adenosine Triphosphate in sympathetic nerves. There is evidence for increased activity of the sympathetic nervous system and the renin-angiotensin system (RAS), as well as a role for NPY in the development and maintenance of hypertension. Angiotensin II (Ang II) is known to facilitate sympathetic neurotransmission; an effect greater in Spontaneously Hypertensive Rats (SHR) than normotensive rats. A newly discovered product of the RAS is Angiotensin (1-7). There is evidence suggesting that Ang (1-7) opposes the hypertensive actions of Ang II. The objective of this study was to investigate the role of Ang II and Ang (1-7) on the nerve stimulated NE and NPY overflow from the mesenteric arterial bed of SHR. Ang II increased the basal and nerve stimulated NPY overflow from the mesenteric bed; an effect that is greater in preparations of SHR than age matched normotensive controls. Preparations obtained from prehypertensive (4-6 week old) SHR appear to behave similarly to those of hypertensive (10-12 week old) SHR with respect to Ang II induced changes in nerve stimulated NPY overflow. This facilitatory effect of Ang II is mediated by the AT1 and the AT2 receptors. In addition, Captopril and the AT1 receptor antagonist EMD66684 decreased neurotransmitter overflow from SHR preparations, suggesting the presence of an active local RAS. In contrast, Ang (1-7) decreased nerve stimulated NE and NPY overflow from mesenteric arteries. This effect was greater in preparations of SHR than WKY. Administration of a Mas receptor antagonist, attenuated the Ang (1-7) induced decrease in NE and NPY overflow. However, the AT2 receptor antagonist attenuated the effect of Ang (1-7) on NE overflow, but not NPY overflow. Moreover, in the presence of L-NAME and Bradykinin B2 receptor antagonist, Ang (1-7) decreased NPY overflow but not NE overflow. Ang (1-7) decreases, whereas Ang II enhances the nerve stimulated NE and NPY overflow from SHR preparations. Therefore, Ang (1-7) may counteract the effects of Ang II by acting on AT2 and Mas Receptors. In addition, our data suggests that Ang (1-7) modulates sympathetic neurotransmission through a nitric oxide dependent mechanism.

Jae Young Kim - North Carolina State University - GSK Award

Calorie restriction (CR), defined as a reduction in energy intake, has been shown to enhance longevity of organisms ranging from yeast to mammals. Under prolonged condition of CR, cells undergo apoptosis.  CR-induced apoptosis is believed to play a positive role on aging by removing damaged and presumably dysfunctional cells (e.g. fibroblasts, hepatocytes). However, the molecular mechanism by which energy depletion induces apoptosis remains unclear.  My research is focused the molecular mechanism by which energy depletion causes apoptosis. I have demonstrated that TAK1 MAPKKK is required for energy depletion-induced apoptosis. I also found that autophagy, which is considered as a protective response to energy depletion, was upregulated in TAK1 deficient keratinocytes. These data suggest that TAK1 controls energy depletion-induced cell death pathway probably by negatively regulating autophagy. I am currently investigating how TAK1 regulates autophagy. In summary, the data implicate that TAK1 determines entrance of autophagy or apoptosis under energy depleted conditions. This TAK1 regulation may be important for longevity.

Anton Kolomeyer - New Jersey Medical School

Age-related macular degeneration (AMD) is the leading cause of central vision loss in the United States among people older than 55 years of age. It is characterized by a number of pathological changes in the eye which negatively affect vision such as retinal pigment epithelial (RPE) cell death and photoreceptor atrophy. RPE cells are critically involved in maintenance of high quality vision as they support the proper function of photoreceptors (i.e., rods and cones). This is accomplished, in part, by producing a number of trophic factors, proteins that diffuse to their target tissues. My project is a systematic elucidation of RPE secretory potential. Reconstitution of proper RPE secretion within a diseased eye might delay and/or prevent the unavoidable loss of vision associated with AMD. 

Daniel Lu - Brown University

The process of aging is an area of biology that is not very well understood. My work seeks to explore single-gene effects (particular the fine regulatory controls of the IMD pathway) on the aging process by manipulating these genes in the fruit fly Drosophila melanogaster and looking for changes in fly lifespan. Because of the strong evolutionary conservation across different organisms, much about the mechanisms of aging in other organisms, including humans, can be discovered through looking at the aging process in flies. Identification of these mechanisms and components and discovering the links and connections to other pathways thought to be involved in aging will increase our pool of knowledge on the overall aging process.

Sophia Maund, Wake Forest University - GSK Award

One in six men will get prostate cancer in his lifetime, and the risk increases with age.  Luckily, there is ample opportunity for prevention due to the slow-developing nature of this disease.  Vitamin D can inhibit prostate cancer cell growth by inducing differentiation or by stopping cell division.  I am interested in vitamin D's mode of action on maintaining normal prostate health by regulating normal prostate cell growth and differentiation.  I am investigating the molecular mechanism of vitamin D-induced differentiation of prostatic progenitor/stem cells.  By targeting specific components of vitamin D-mediated differentiation, I aim to potentiate the chemopreventative effects of vitamin D.

Joana Soares, University of North Carolina at Chapel Hill - GSK Award

Aging involes a progressive deterioration of tissue function, in part due to a reduction in new growth and a diminished capacity of tissue repair. Mounting data support the notiont hat the loss of telomere repeats ins tem cells and lymphocytes contribute to human aging. Althoug telomere loss occurs naturally with each round of DNA replication, telomere shortening can be intensified by the presence of reactive oxygen species due to oxidation of telomeric DNA. My research focuses on demonstrating that oxidaive stress can not only shorten telomeres directy by producing DNa damage, but it can also oxidize a critical cysteine residue fo the protein subunit of telomerase, threfore, limiting its capability of forming an active telomerase complex adn thus extending telomeres. This research is relevant for elucidating the crucial roles of oxidative damage to telomeres and telomerase in cellular agin and in understanding the underlying principles of the aging process.

2007

Jessica Siegel - Oregon Heath and Science University

Healthy aging and aging with Alzheimer’s disease are both characterized by cognitive impairments and deterioration of the brain acetylcholine receptor system. The acetylcholine cells that lose their receptors in aging and Alzheimer’s disease are largely involved in learning, memory, attention, and cognition. There is a higher rate of Alzheimer’s disease amongst women as compared to men. Furthermore, people carrying the apolipoprotein E4 allele also show higher rates of Alzheimer’s disease development. Using receptor binding assays, I am examining the effects of age, sex, and apolipoprotein E genotype on acetylcholine receptors in the brain using a mouse model. Results from my research will determine differences in the extent of acetylcholine receptor loss in aging between males and females and between the different apolipoprotein E genotypes. This research will help us to better understand the contribution of these factors on acetylcholine receptor changes, bringing us one step closer toward developing more effective therapies for age- and Alzheimer’s disease-related cognitive impairments.

Zhaoyu Wang - University of Wisconsin 

Cancer is now America’s real No. 1 killer disease. Life expectancy has increased dramatically and aging is a high risk factor for cancer. My interest is in cancer research such as endometrial cancer. One of our approaches is through proteomic analysis that quantitatively profiles protein expression and finds out which signaling pathways may be altered in cancer. The study will help us better understand not only the biological mechanisms of the disease, but also guide future directions in advancing our knowledge in this very important area of research.

Yi Zhang - North Carolina State University

Nervous system disorders such as epilepsy, Huntington’s, Alzheimer’s, and Parkinson’s in the elderly population are creating huge family, social, and economic burdens. The ability to restore neuron and glial cells within the nervous system will aid therapies for nervous system diseases and injuries. My research focuses on identification of genes and signaling pathways involved in neuron and glial development and neuron-glial interactions, which may provide cues for the restoring process. Based on the conservation of genetic control for many aspects of the nervous system development between invertebrates and human, I take advantage of the Drosophila midline, a functional analog of the floorplate cells in vertebrates, as a model system to study how different types of neurons and glia specified and differentiated. My results suggest that in Drosophila midline the extrinsic factors - signaling pathways provide positional information first, and then the intrinsic factors such as transcription factors define each precursor’s fate.

2006

Rebecca Bish, Cold Spring Harbor Laboratory

Our DNA is constantly subjected to damage from a variety of sources, including environmental toxins and free radicals generated by normal cellular metabolism. The cell maintains an elaborate system of proteins devoted to repairing DNA damage. Unrepaired DNA damage contributes to cancer, neurodegeneration, and other aspects of aging. My research has uncovered the mechanism by which an entire family of DNA repair proteins is recruited to the site of DNA damage. I have also demonstrated that a previously uncharacterized protein in this family plays an important role in DNA repair. Interestingly, this family of proteins is closely linked to several progeroid diseases, which are characterized by accelerated aging. This research has implications for our understanding of the role of DNA repair in the aging process, and for the treatment of cancer and other age-related ailments..

John Robert Coleman - Stony Brook University

The degenerate nature of the genetic code allows for multiple ways to encode a given gene.  This phenomena due to the presence of synonymous codons for a single amino acid, for example the amino acid arganine has six corresponding codons.  With the burgeoning technology allowing us to synthesize large pieces of DNA in vitro and combining this technology with computer-based algorithms, the synonymous encoding of a gene can now be altered.  This alteration maintains the amino acid sequence of the gene but shuffles the codons.  This shuffling is done to create novel codon-pairs, with the goal of slowing the genes rate of translation.  This codon rearrangement was applied to the genes of poliovirus in order to slow the virus’ growth, with the goal of creating a vaccine.  Thanks in part to the support of AFAR, this work produced successful results; yielding a significantly weaker poliovirus and a model for future vaccines.  This work appeared in the June 27 2008 issue of Science. 

Fatih Mercan - Yale University

Muscle injuries occur more frequently in older people with decreased locomotive abilities. Muscles normally have the capacity to repair themselves with the help of muscle stem cells called satellite cells, but this capacity declines with age. Before injury, satellite cells remain in a non-proliferating state. However, upon injury, activated satellite cells proliferate and migrate to the site of injury to help regenerate the injured muscle. Our studies have found the enzyme, Mitogen Activated Protein Kinase Phosphatase-1 (MKP-1) as a major regulator of satellite cell activation. We found that in the absence of MKP-1 muscle repair is seriously impaired because of a defect in satellite cell activation. This research will help us understand the muscle repair mechanism in detail and will consequently lead to the development of therapeutics that will increase muscle repair capacity in older people.

Tony Tu - Duke University

Tony is a graduate student at the University of Chicago. He received his award when an undergraduate student at Duke University.  He is studying and characterizing the DNA release from tumor cells killed by antibody mediated complement.  Information about the amount of DNA released in correlation with size, origins and mechanism of release is necessary to establish DNA as a biomarker. 

2005

The functioning of the prefrontal cortex (PFC) is instrumental in the organization and execution of thoughts, emotions and actions. The hallmark operation of the PFC is working memory or representational knowledge-the ability to represent information in the absence of stimuli.  This ability ultimately permits us to follow a train of thought, remember where we just put your house keys, or inhibit inappropriate or distracting stimuli. Although there is a well-documented profile of age-related PFC decline from both human and animal studies, molecular and electrophysiological studies of the aged brain in animals have primarily focused on the hippocampus. Developing therapies to improve cognitive function and quality of life among the growing elderly population requires more research on mechanisms of age-related PFC decline. AFAR has contributed to my research on anatomical and cellular mechanisms of PFC decline in aged rats. 

I am currently working on projects in aged and young-adult rats that combine a variety of methodologies including: 1) quantitative morphometric methods designed to assess the status of dendritic architecture and spine density in PFC neurons, 2) cognitive-behavioral studies of PFC functioning, and 3) manipulations of noradrenergic receptors or intracellular signaling cascades that may be implicated with PFC decline. Together, these methods permit me to examine structure-function relationships in the aged and young PFC, and will ideally identify factors that impact the operations of PFC networks and contribute to age-related PFC decline.

In addition to providing me with direct support for these projects, AFAR has also provided valuable opportunities to connect with other members of the age-concerned scientific research community. I look forward to following the progress of AFAR-related projects and I am grateful to have been connecting with such a supportive and progressive organization so early in my research career. Thank you!

Emily Davies, Duke University 

Emily's research involves diabetic retinopathy and how marrow-derived cells contribute to the homeostatic modeling of the ocular perivascular environment. Her research will enhance the understanding of how progenitor cells might be used therapeutically for ocular vascular diseases. 

David Lamar, Emory University

David is studying the mechanisms underlying decreased immune function in the aging population.  He is examining the functional integrity of of aged T (immune) cells using organismal, cellular and molecular approaches. 

I am grateful to AFAR for funding my current undergraduate research project. Low back pain is the most prevalent cause of activity limitation in Americans under 45 years of age and results in at least $50 billion dollars in annual health care costs. By understanding the factors that effect magnetic resonance image maps of intervertebral discs, a better assessment of this diagnosis method can be made. Further, it will not only aid in diagnosis but also aid in determining the optimal course of treatment.

2004

David Arthur - University of California - San Diego

The AFAR award contributed to research on age-related neuronal degeneration of the periphery.  There is a great void in the available literature regarding the mechanisms of the loss of motor function associated with a decline in neurotransmission as part of the natural aging process.  My research, under the guidance of Paul Insel, M.D. (UCSD), focused on the role of nucleotide receptors, with particular attention to P2X receptors in a cellular model of age-induced neurodegeneration.  Our lab demonstrated changes in receptor expression following decline in chemicals that support the survival of neurons.  This change in receptor expression may be a contributing factor in the loss of sensation and control of peripheral innervation targets as neurotrophin levels decline with age.  

2003

Matthew Allen - Northwestern University

Alzheimer's disease is a debilitating disease that affects over four million Americans. It is characterized by psychological symptoms and the presence of plaques in certain parts of the brain. My research focuses on the detection of Alzheimer's disease using magnetic resonance imaging (MRI). MRI is a noninvasive method of acquiring 3-dimensional internal images. I am using chemistry to connect a molecule which sticks to the plaques involved in Alzheimer's disease to an MRI contrast agent. This would allow for imaging of the plaques during a patient's lifetime. Currently, the plaques are not discovered until an autopsy is performed. I have synthesized a series of promising contrast agents and am presently testing the viability of the agents using cells, brain slices, and mice. If successful, this research will lead to early, accurate diagnosis of Alzheimer's disease.

2002

Barry Flanary - University of Florida

Microglia and Alzheimer's Disease

Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive degeneration and death of neurons in brain regions involved in learning and memory. An age-specific incidence rate exists such that AD incidence doubles every 4.4 years after age 60. AD afflicts 1 in 10 individuals over age 65 and nearly half of those over age 85. Neurons are a specific type of cell that are dispersed throughout the central nervous system (CNS: the brain and spinal cord) and function by relaying messages to and from the brain and storing memories. However, the majority of cells in the CNS are not neurons, but glia. Microglia are one type of glia that are distributed ubiquitously throughout the CNS and function by supporting the normal function of neurons and by maintaining homeostasis within the CNS microenvironment. Neurons, which do not undergo cell division, are supported by microglia, which do divide by division. Over time, as telomeres in dividing microglia shorten, these cells may enter senescence and become dysfunctional. As a result, the microglia may be less able, or unable, to maintain neuronal health. As a result, when sufficient amounts of microglia have senesced, the neurons they once supported begin to degenerate, enter senescence, and ultimately die as well. Neuronal cell death leads to loss of communication between neighboring neurons, and ultimately is the cause of memory loss evident with age and in AD.

Current Research Goals:

The current focus of our work is to provide a better understanding of the roles that microglial telomere shortening and senescence plays in normal aging and in the development of AD. This is a novel area of research in AD, and no previous research has been performed in this area. We hypothesize that telomere shortening occurs in microglia over time and with normal aging. This leads to their senescence and contributes indirectly to neuronal cell death. Our short-term goals are to study telomere length and telomerase activity in rat microglia both in vitro (cells grown in a culture dish) and in vivo (cells living within an organism). Our long-term goals are to study telomere length and telomerase activity in human microglia (from non-demented and AD individuals) in vitro and to over-express telomerase in rat microglia in vitro to determine whether this prevents telomere shortening and senescence in these cells. If telomere shortening in microglia can be delayed or prevented, then this may enable these cells to delay or prevent their entry into senescence. Thus, if senescence can be avoided, microglia should be able to live longer than normal and be able to provide additional support to neurons, thereby slowing their death as well. Therefore, if telomere shortening in microglia can be delayed or prevented, then AD may also be delayed or prevented.