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Joseph A. Baur, PhD
Instructor
University of Pennsylvania School of Medicine

Does Mitochondrial Biogenesis Regulate Longevity?

Many interventions that improve health and longevity such as a calorically-restricted diet also increase the number of mitochondria in cells. Mitochondria provide the energy for cells to process nutrients and, as a result, produce free radicals thought to cause aging and disease. But increased mitochondria in cells may actually decrease the harmful effects of free radicals since the energy needs of the cells may be less stressed if the work is shared among more mitochondria. Dr. Baur will test the hypothesis that extra mitochondria can account for some of the beneficial effects of caloric restriction at the cellular level, and that stimulating the production of extra mitochondria may be a way to alleviate age-related degeneration in humans.

Stephanie J. Bryant, PhD
Assistant Professor of Chemical and Biological Engineering
University of Colorado

Elucidating the Role of Biomechanical Factors in Age-related Changes in Cartilage: A Possible Risk Factor for Developing Osteoarthritis

Osteoarthritis - which is a degenerative joint disease - is a common disease of aging. More than 50% of people over the age of 65 are estimated to have some evidence of the disease. Abnormal mechanical forces caused by obesity, previous joint injury or joint misalignment in combination with aging, are thought to be a cause. Dr. Bryant will investigate the mechanisms of cartilage cell degradation involved in tissue elasticity to determine whether tissue degradation caused by abnormal mechanical forces is a risk factor for developing osteoarthritis in adult cartilage. She will also investigate whether younger cartilage may have some protective benefits against the condition. If successful, the knowledge gleaned from Dr. Bryant's research may help to identify ways to slow the progression of osteoarthritis and offer better treatments to those who have it.

Xin Chen, PhD
Assistant Professor
The Johns Hopkins University

Histone Turnover During Stem Cell Homeostasis and Aging

It is becoming clear that adult stem cells help repair many organs such as muscle, brain, and heart as we age. However, stem cells are very difficult to study in most animals. Dr. Chen takes advantage of recently discovered adult stem cells in the fruit fly, an animal in which stem cells are remarkably easy to study, to investigate how stem cells maintain their ability to produce healthy new cells even as animals age, particularly focusing on how proper regulation of their genes is passed on to new "daughter" cells. The knowledge gained in Dr. Chen's study could ultimately help us develop stem cell therapies for a host of age-related diseases.

Heng-Jie Cheng, MD, PhD
Assistant Professor
Wake Forest University Health Sciences

Upregulation of Beta3-Adrenoceptors: A New Mechanism For Age-Dependent Decline in Cardiac Function and Beta-Adrenergic Reserve

Heart disease is the number one killer and major cause of disability among Americans. Part of the problem with an aging heart is that heart cells gradually decrease their ability to contract. Dr. Cheng will test the idea that the loss of heart contractility is due to a molecule which appears with increasing frequency on the surface of aging heart cells. If true, then pharmaceutically blocking the activity of this molecule could preserve heart function in later life, thus saving lives and preserving health.

Audrey L. Duarte, PhD
Assistant Professor
Georgia Institute of Technology, School of Psychology

The Effects of Aging on Associative Memory

While the majority of research examining memory changes in healthy older adults has focused on declines in performance and related brain activity, Dr. Duarte's project will focus on the types of memories that may be preserved or even enhanced as people age. The results from these experiments will provide a better understanding of the functional and structural organization of associative memory and allow better characterizations of healthy age-related changes. Such results may help inform future research to distinguish healthy from pathological brain aging, such as in Alzheimer's disease.

Jeffrey L. Dudycha, PhD
Assistant Professor
University of South Carolina

The Genetic Basis for the Evolutionary Divergence of Aging

Much of aging research genetically modifies laboratory animals to investigate the mechanisms that underlie different aging rates. Dr. Dudycha proposes that we can also learn a great deal possibly about novel aging mechanisms by investigating the genes underlying natural variation in aging rate among a variety of species. His evolutionary studies may lead to the discovery of new genes involved in natural aging. These genes could then be the target of new kinds of medications to combat the ravages of aging in humans.

Martin L. Duennwald, PhD
Scientist
Boston Biomedical Research Institute

The Systems Biology of Age-Dependent Protein Misfolding

A number of age-related neurological diseases such as Alzheimer's disease and Parkinson's Disease seem to be caused by misfolding of otherwise normal proteins inside brain cells. Proteins to perform their normal function have complex folding patterns like origami, and if normal folding is disrupted not only fail to perform their normal functions but can become toxic. Dr. Duennwald hopes to learn what complex molecular changes occur inside aging cells lead to increased protein misfolding by introducing proteins causing human diseases into aging yeast cells. Yeast cells are among the most powerful tools we have for dissecting the causes of complicated molecular events. In doing so, Dr. Duennwald hopes to discover previously unidentified molecular pathways that affect protein misfolding. His research could thus provide new insight into the basic biology of protein misfolding, which could inform future research and possibly treatment of human neurodegenerative diseases.

Susan A. Krum, PhD
Assistant Professor
University of California, Los Angeles

Gene Regulation by Estrogen in Adipose of Aging Bone

Dr. Krum is studying the role estrogen plays in regulating bone and fat cells. More than 10 million Americans - most commonly post-menopausal women -- have osteoporosis. While estrogen provides protection against bone fractures by increasing bone mass and lowering fat accumulation, the mechanism by which it does this is unknown. Learning more about estrogen function could aid in better bone health, reducing the debilitating effects of fractures in the elderly.

Jonathan H. Lin, MD
Assistant Professor
University of California San Diego

Cellular Responses to Chronic Protein Misfolding

Protein misfolding underlies many age-related diseases including Alzheimer's disease, Parkinson's disease and macular degeneration. Dr. Lin will research the mechanisms by which human cells cope and adapt to protein misfolding or die. This may shed light into the pathogenesis of age-related diseases which could lead to new therapies to target these mechanisms.

Goldis Malek, PhD
Assistant Professor
Albert Eye Research Institute

Osteopontin Regulation of Choroidal Neovascular Fibrosis through Macrophages

Age-related macular degeneration (AMD) is a leading cause of vision loss in Americans 60 years of age and older. It occurs in two forms: wet and dry. Wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula - the part of the retina that allows people to see in small detail -- often causing the leaking of blood and other fluid. This causes rapid damage. Dr. Malek's research seeks to determine how macrophages - white blood cells that removes foreign materials and which are present in the membranes and retina of patients with wet AMD -- contribute to the severity of new vessel growth. Her research will focus on the protein osteopontin, a regulator of inflammation in the eye, and how it might serve as a signal attracting and retaining macrophages to the site of injury in the eye. If validated, Dr. Malek's research could provide a potential therapeutic target for wet AMD.

James R. Mitchell, PhD
Assistant Professor of Genetics and Complex Diseases
Harvard School of Public Health

Testing Small Molecule Inhibitors of GH/IGF-1 Receptor Signaling as Dietary Restriction Mimetics Against Acute Stress in vivo

Dr. Mitchell's research seeks to understand the role that growth factor signaling plays in the regulation of lifespan and stress resistance. Decreased growth factor signaling through genetic and dietary means (caloric restriction) may play a part in the beneficial effects seen in extended lifespan and increased stress resistance in a wide range of organisms including mammals. Through the use of compounds that mimic the beneficial effects of caloric restriction without reducing food intake, Dr. Mitchell will test the ability of small molecule inhibitors of growth factor signaling to increase resistance to acute stress in experimental rodents. The longer-term goals of his research are to determine whether reduced growth factor signaling will also protect against organ failure during surgical procedures that require stopping blood flow to an organ to prevent bleeding. Dr. Mitchell's research could shed light on the mechanisms underlying improved stress resistance in the setting of unavoidable surgical stress.

Raul Mostoslavsky, MD, PhD
Assistant Professor
Massachusetts General Hospital Cancer Center, Harvard Medical School

SIRT6, a Chromatin Regulator of Glucose Homeostasis and Genomic Stability

Dr. Mostoslavsky will investigate whether SIRT6 modulates glucose metabolism and DNA repair and whether this function is important in modulating aging and age-related diseases. Cells require glucose to provide energy for metabolic activity and are able to trigger an adaptive response to ensure their survival under conditions of nutrient stress. Recent research on the beneficial effects of the sirtuins on lifespan has focused on lower organisms, but it is not clear if those results will translate to mammals. Dr. Mostoslavsky will try to define the molecular function of the SIRT6 protein in glucose homeostasis and DNA repair. Understanding this process could provide an opportunity to control its activity, possibly offering therapeutic benefits against type II diabetes, cancer, and other common diseases of aging.

Nicolas Rohleder, PhD
Assistant Professor
Brandeis University

Determinants and Consequences of the Acute Stress-induced Inflammatory Response in Human Aging

Rates of aging may be affected by how people handle stress. Dr. Rohleder's research will test the healthy and unhealthy response patterns of older adults to stress to determine if specific patterns affect biological, emotional and cognitive aging. One focus of the project will be the acute stress response of the inflammatory system, which has been associated with age-related diseases such as cardiovascular disease, type 2 diabetes, osteoporosis and some forms of cancer. The project will serve as the basis for a longitudinal study in which participants are tracked for up to five years to test long-term health consequences of specific response patterns. Understanding the effects of stress may allow for better preventative interventions that could result in healthier aging.

David W. Walker, PhD
Assistant Professor
University of California, Los Angeles

Investigating the Life-extending Mechanisms of Apolipoprotein D: An Evolutionary Conserved Modulator of Oxidative Stress and Aging

In fruitflies, mice and plants, Apolipoprotein D (ApoD) -- a gene that has been linked to a number of age-related diseases in humans, including Alzheimer's disease -- may play a role in protecting cells against free radicals and oxidative stress. Previous studies showed that ApoD can extend lifespan when activated in all cells and tissues. Dr. Walker will study the role ApoD plays in the regulation of lifespan using genetics, molecular biology, and whole organism physiology. He will study the impact of targeted expression of ApoD to specific cells and tissues at specific intervals in the animal's lifetime. He will also investigate the relationship between ApoD and the insulin/IGF-1 signaling pathway, an evolutionary conserved determinant of longevity. The long-term aim of his work is to provide effective therapeutic targets to treat or prevent age-related diseases.

Shuanhu (Joe) Zhou, PhD
Instructor
Brigham and Women's Hospital

The Effects of Niche on Mesenchymal Stem Cells During Human Skeletal Aging

Bone fractures are a major source of disability among the elderly. Bone is a living tissue which deteriorates with aging due to an imbalance between the activity of cells that continuously produce new bone and cells which reabsorb old bone. Cells which produce new bone are produced by a type of recently discovered adult stem cell. Dr. Zhou's research will investigate how the aging cellular environment of these stem cells may contribute to their declining ability to produce new bone-producing cells. This information could be important in developing methods for keeping adult stem cells healthy longer which in turn could keep our bones healthy longer.

AFAR Affiliate Research Grant Program

Yongjie Zhang, PhD
Senior Research Fellow
Mayo Clinic College of Medicine

Generation and Characterization of M337V TDP-43 Transgenic Mice: A Possible Model For TDP-43 Proteinopathy

Dr. Zhang will develop a novel transgenic mouse model of Amyotrophic lateral sclerosis (ALS). The model will express a nuclear protein called TDP-43 which is known to clump abnormally in a number of degenerative diseases. A mutation of the TDP-43 protein called M337V has been identified in young individuals from two unrelated families with a strong history of ALS and research in chick embryos, demonstrated that it caused neurons to die. Dr. Zhang will study how TDP-43 with the M337V mutation causes ALS. A greater understanding could lead to earlier biomarkers for diagnosis of the disease.

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