Awardees By Year
2011 Biology of Aging Grant Summaries
Epigenetic profile in aging and healthy life span
Epigenetics—heritable changes in gene function that do not involve changes in DNA sequence—have revolutionized the concept of genetics affecting disease risk. Epigenetics have been found to be associated with cancer risk and autoimmunity disorders. Moreover, epigenetic changes at specific sites appear to increase with age. Hence, they may serve as indices for chronological age. Using the Ashkenazi centenarian cohort (1 in 5,000 in the human population), Dr. Atzmon and his team will test the hypotheses that epigenetic changes associated with aging could serve as markers for healthy lifespan, and that these changes may represent one of the central mechanisms by which aging predisposes us to many age-related diseases.
The regulation of mucosal immunity to influenza virus in the aged NALT
Each year, influenza viruses cause significant illness and death in the elderly. Dr. Baaten will investigate the responses that bring about the development of immunity in the nasal mucous membrane after influenza virus immunization. Preliminary tests on mouse models show that antiviral T cell responses in the aged nasal-associated lymphoid tissue (NALT) are reduced. CD8 T cells are crucial for curing influenza, can protect from divergent viruses, and are highly correlated with protection in the elderly. Their reduced number in the NALT correlates with increased susceptibility to influenza in older people. Possible reasons for this decrease in CD8 T cells include impaired induction of the T cells, changes in the NALT inflammatory environment, or changes in the aged T cells’ ability to migrate into the nasal mucous membrane. Dr. Baaten will work to determine if these aspects are affected. His findings could lead to the improvement of nasal influenza vaccines.
Neuronal Aging: Interactions between Neuronal Protection Regulators and Life-Extending Pathways
Aging brings about dramatic changes in the physiology of the brain, including an increased incidence of age-related cognitive decline and neurodegenerative disorders. The mechanisms by which aging triggers these conditions are largely unknown. Dr. Bénard’s project will examine how brain cells age, how brain function is affected, and how this in turn relates to the aging of the whole body. The project’s main goal is to uncover strategies to counteract age-related brain decline. This research could impact the treatment of neurodegenerative diseases and the development of approaches to improve the effects of aging on cognition, thus improving quality of life for the elderly.
12/15-lipoxygenase pathway derived lipid mediators in the regulation of age-related muscle atrophy
Aging is associated with a progressive loss of muscle mass, which is characterized by a loss of muscle fibers and fiber atrophy that leads to functional impairments, significantly reduces quality of life, and increases the risk of morbidity and mortality in the elderly. Among other factors, loss of innervation of muscle fibers and an increase in pathways that increase muscle protein degradation are believed to play a significant role in muscle atrophy. Dr. Bhattacharya’s studies aim to increase our understanding of the lipid signaling pathways that regulate protein degradation during loss of muscle innervation in aging, and to provide the basis for designing interventions to slow or ameliorate the effects of aging on muscle structure and function.
Study of Reproductive Signals that Regulate Aging
While much is known about how aging reduces fertility, the impact of reproduction on aging is poorly understood. Dr. Ghazi will identify and study the genes that allow reproductive tissues to alter the rate of aging in C. elegans. Removing reproductive cells called Germline Stem Cells (GSCs) in C. elegans results in increased lifespan. Similar studies in flies and mice have indicated that reproductive influences on aging may be widely prevalent in nature. The extended lifespan obtained by GSC removal in worms requires a universal pro-longevity protein called DAF-16/FOXO to be present in intestinal cells. Dr. Ghazi discovered that TCER-1, the worm counterpart of a human protein, regulates DAF-16/FOXO activity specifically following GSC removal. These findings begin to explain how reproductive tissues control the rate of aging. They emphasize the significance of the worm intestine, which shares many features with the human intestine, as a coordination center for determining longevity. Dr. Ghazi plans to use TCER-1 and DAF-16/FOXO as molecular tools to understand the dialogue between reproductive and somatic tissues, including what events occur in the intestine to alter lifespan and how the intestine relays longevity signals to the rest of the body.
Omega-3 Fatty Acids: Opportunities as Aging Countermeasures
Mitochondria produce energy in cells, but these organelles lose function with aging. Aging also decreases responsiveness to insulin. While exercise protects against these age-related declines, it is critical to identify alternative therapies for people who cannot exercise. Early evidence shows that the fats found in fish oil improve mitochondria and increase insulin sensitivity. The goal of Dr. Lanza’s project is to determine how fish oils may improve mitochondrial function and insulin action in young and old mice. The research could lead to an increased understanding of protein metabolism with aging and identify several new therapeutic benefits of fish oil supplementation for older people.
Changes in auditory cortical circuitry in aging: Exploration of the links between aging and the cortical circuitry of attention.
Age-associated hearing loss affects approximately one-third of older adults. Though great strides have been made to restore hearing with hearing aids, most listeners continue to complain of difficulty understanding speech in real-life environments. This can significantly impact their ability to remain fully socially engaged. Dr. Llano and his team believe that the root of this difficulty is the inability to suppress distracting information, caused by the dysfunction of certain sets of inhibitory neurons. They will test this idea by examining changes in the network circuitry of the auditory system in aging animal models. This research can lead to a better understanding of the mechanisms of age-related hearing loss, and may provide potential therapeutic targets to ameliorate this loss.
The role of microRNAs in stem cells of the aging hematopoietic system
Aging is associated with a functional decline in blood stem cells, which results in decreased red cell and immune cell production and an increased risk of developing blood disorders including acute myeloid leukemia (AML) and the myelodysplastic syndromes (MDS). Small RNA molecules known as microRNAs (miRNAs) regulate blood stem cell function. The dysregulation of these miRNAs may thus underlie the changes observed in the aging hematopoietic system. Dr. Park will study the expression and function of miRNAs in the blood stem cells of normal elderly patients or aged animals. Dr. Park anticipates that his investigations will lead to the discovery of new principles that may explain normal aging, as well as the predilection for AML and MDS to develop in the elderly.
Regulation of kidney glycosphingolipid metabolism by caloric restriction during aging
Kidney function progressively declines during aging, making the elderly more susceptible to toxic side effects from medications typically used to treat a wide variety of age-associated diseases. Chronic kidney disease and end-stage kidney disease are also more prevalent in the elderly than in younger adults. Caloric restriction (CR) is the only known intervention to preserve kidney function during aging. Dr. Siskind will test the hypothesis that caloric restriction maintains kidney function during aging by regulating sphingolipid metabolism. She will do so by identifying the specific enzymes in the sphingolipid pathway that are regulated by CR—and the mechanism by which they are regulated—with the long- term goal of developing CR mimetics for use in the elderly.
In vivo studies of age-related decline in synaptic plasticity
Aging is accompanied by a progressive decline in cognitive and learning ability. Synaptic loss, one of the hallmarks in normal aging, likely plays an important role in cognitive impairments in the aged brain. Dr. Yang will examine learning-associated synaptic remodeling with transcranial two-photon microscopy in the living cerebral cortex of young adult and aged mice. She will test the hypothesis that the decline of learning and memory with age is associated with the reduction in learning-induced synaptic remodeling. She will also examine whether environmental enrichment ameliorates age-related decline in learning-induced synaptic plasticity. This research will establish the important link between synaptic deficits and learning impairments in aged brains and provide evidence for the effectiveness of environmental enrichment in reversing age-related synaptic defects.
Age-related dysregulation of the sympathetic nervous system and blood pressure; the role of hydrogen peroxide
As people age, their risk for cardiovascular diseases increases. Baseline blood pressure (BP) and sympathetic nervous system (SNS) activity increase with age, while baroreflex sensitivity and circadian fluctuation of BP and heart rate (HR) decrease. Research shows that excessive levels of hydrogen peroxide (H2O2) in hypothalamic and brain stem regions may play a central role in age-related dysregulation of the SNS and BP. Dr. Erdos has demonstrated that levels of catalase, an enzyme that scavenges H2O2, decrease markedly in the hypothalamus and brain stem with age. In addition, H2O2 has been shown to affect SNS regulatory mechanisms in certain areas of the brain stem. By equipping young and old rats with radiotelemetric transmitters to measure BP, HR, and sympathetic nerve activity, Dr. Erdos will test the hypothesis that reduced expression of catalase and elevated levels of H2O2 in the brain stem play a significant role in age- related reductions in baroreflex sensitivity and circadian BP variability. His findings could lead to new approaches for treating hypertension and cardiovascular diseases in the elderly.
Stress vulnerability and post-stroke cognitive decline
Recent studies have shown a relationship between elevated stress hormone (cortisol) and memory decline in older adults. However, the exact role of chronic stress in developing cognitive changes associated with aging, degenerative illnesses and stroke is less clear. The project aims to test potential biomarkers, saliva and hair cortisol, as predictors of cognitive impairment and dementia following stroke. The identification of biomarkers to predict cognitive decline in aging populations has important clinical implications. Dr. Ben Assayag will perform a prospective study of 100 first ever acute ischemic stroke patients who will be followed for 18 months and 30 age- and gender-matched healthy controls. Measurements will include saliva and hair cortisol, psychological and neuroimaging measures as well as neurological and cognitive scores.
Electrophysiology of Category Learning in Mild Cognitive Impairment
The ability to learn and use categories is a fundamental property of the human memory system. Past neuroimaging studies have suggested that rule-based category learning is critically dependent on brain regions frequently associated with Mild Cognitive Impairment and Alzheimer's disease. Dr. Morrison plans to study age-related changes in rule-based category learning as it may be particularly sensitive to neurocognitive changes seen in MCI and AD. Dr. Morrison hopes to develop a simple, cost-effective method that can be used as part of an early screening program beginning in middle age to select people for remediation strategies before major neural damage.
β2 adrenergic receptors as mediators of the Aβ-induced cognitive decline
Alzheimer's disease is characterized by two types of protein aggregates, neurofibrillary tangles (tau) and amyloid plaques. The goal of this proposal is to dissect the molecular pathways linking Aβ accumulation to cognitive deficits. Dr. Oddo hypothesizes that the buildup of Aβ leads to cognitive deficits by increasing the activity of the mammalian target of rapamycin (mTOR) via β2 adrenergic receptors. The mTOR pathway is emerging as a key regulator of aging and since Aβ is clearly one of the pathogenic molecules direct linked to AD pathogenesis and is observed at very early stages of disease progression, understanding the link between Aβ and cognitive decline is highly significant.
Dietary factors, inflammation and cognitive decline in diabetic elderly
Dr. Ravona-Springer’s study aims to examine the relationship of dietary factors, particularly different Vitamin E (tocopherol) forms, dietary fats (saturated and trans fat, MUFA and PUFAs), and dietary patterns with cognitive deterioration. It will leverage on an ongoing study of well-characterized diabetics in Israel. In the parent study, a cohort of more than 1400 diabetic, cognitively intact subjects aged 65 and above, has been established. The cohort will be followed every 18 months, for 5 years, with broad cognitive and functional assessments. Multiple diabetes related factors (such as age of diabetes onset, co-morbidities, medications, diabetes-related complications, etc.) are recorded. Given the explosive rise in obesity and diabetes, a better understanding of modifiable risk factors for cognitive decline in this high risk older population is of clinical importance. Both diabetes and cognitive decline are very common in the elderly and the relationship among these two co-morbidities has been reported. However, the association has been hard to dissect, i.e. cause/effect, mechanisms, etc. so this work may lead to important findings.
Neuronal Trafficking and Metabolism of key proteins in Alzheimer's disease and novel intervention strategies
A key feature of the age-related neurodegeneration seen in Alzheimer's disease is the deposition of protein fragments called beta-amyloid in brains of patients. The precise pathway by which this protein is deposited in diseased brains is of exceptional interest as interfering with this process would lead to a reduction of the beta-amyloid deposits and possible relief of symptoms of Alzheimer's disease. Though many previous studies have looked at the pathway by which beta-amyloid is generated, the vast majority of studies have not focused on the nerve cell (neuron) where these fragments are actually generated in the disease, but instead have evaluated this pathway in non-neuronal cells. This is mainly due to ease of experimentation in non-neuronal cells however inferences from these types of cells (which are widely accepted by the scientific community) have not been carefully validated in neurons.
Dr. Roy has developed new state-of-the-art imaging tools that will allow his lab to look at this pathway in detail within living neurons. Upon completion, Dr. Roy's studies should provide a much clearer view of the neuronal pathways that result in the generation of beta-amyloid. In addition, he also proposes a new way to inhibit the beta amyloid in neurons that may lead to new therapeutic targets in Alzheimer's disease.
The role of muscle dependent changes in lipid metabolism upon dietary restriction in Drosophila melanogaster
Dietary restriction (DR) extends lifespan and protects against a number of age-related diseases, including neurodegeneration, cancer, diabetes, and cardiovascular diseases. Using Drosophila melanogaster (common fruit fly) as a model, Dr. Kapahi aims to identify mechanisms by which DR slows aging and age-related diseases. He plans to demonstrate that DR enhances fatty acid metabolism, which leads to increased muscle activity and extends lifespan in the fly. He will also address the mechanisms by which changes in fat metabolism in the muscle tissue play a causal role in mediating the lifespan extension effects due to DR. His findings can significantly increase our understanding of the role of nutrition in aging and age- related diseases in humans./p>
Re-balancing TGF-beta signaling in aged Alzheimer’s rats
Dr. Town and his team will use a novel rat model of Alzheimer’s disease (AD) to determine whether a drug that re-balances inflammation can halt or even reverse age-dependent disease. Though it is difficult to develop drugs that cross into the brain from the blood, Dr. Town’s team will administer the blocking drug into the periphery to target peripheral immune cells, called macrophages. The drug causes these macrophages to enter into the brain from the blood, where they remove the “senile” amyloid plaques associated with AD and may therefore halt injury to brain cells. The research has three goals: to determine whether the blocker drug can prevent AD pathology in the Alzheimer’s rats, to determine whether the inhibitor drug can actually treat disease after it is already present in Alzheimer’s rats, and to understand the mechanism for how these macrophages help fight the disease.
Dissection of the Stochastic Mechanisms Underlying Differential Longevity in lsogenic Populations of C. elegans
For many diseases, biomarkers have been established that facilitate rapid detection and subsequent clinical intervention. However, few—if any—"biomarkers of aging" have been determined. In 2005, Dr. Johnson and his team put forth just such a marker: expression of a "reporter” of HSP-16.2, a small protein that is expressed in response to heat stress. On the second day of adult life, the team can predict whether an individual will live a long or short life. They make the prediction by measuring the brightness of HSP16, which has been made into a visual biomarker in C. elegans by using genetic engineering to put this "reporter” into the worm. Such knowledge of future health prospects well before problems are encountered can help physicians decide on appropriate medical interventions for a patient. This research could also lead to the understanding of why life-threatening events occur and help bolster patient defense systems to allow survival.
Mechanisms for the early pleiotropic actions of IFG-1 on aging
Insulin-like Growth Factor (IGF)-1 is an important circulating protein that decreases with age. The age-related decline in IGF-1 has been associated with disability and loss of function in many organs and tissues, and replacement of IGF-1 to older animals and humans restores function. However, studies in many species have shown that lifelong deficiency of IGF-1 increases lifespan. The bases for these conflicting results are unknown. Dr. Sonntag will assess whether early life (neonatal) IGF-1 deficiency differs from adult-onset IGF-1 deficiency on three endpoints: local (tissue) IGF-1 expression, glucose regulation, and inflammatory responses. These studies will represent the most comprehensive analysis of the effects of IGF-1 deficiency on metabolism, oxidative damage, pathology, and lifespan thus far.
Assistant Professor of Medicine
University of Wisconsin School of Medicine and Public Health
Cognitive outcomes and neuropathology in older adults following critical illness
Critical illnesses that require treatment in an intensive care unit, such as respiratory failure and life-threatening infections, are very common in the United States, and individuals 65 years old and older are at the highest risk of suffering such illnesses. More and more people are surviving because treatments for critical illness have improved in recent decades, but many people suffer significant health problems that arise from these illnesses and their treatment. Numerous studies have demonstrated that cognitive impairment following critical illness is common and often permanent. Since age is the strongest risk factor for dementia in general, older individuals may be at increased risk for significant cognitive impairment after critical illness. Dr. Ehlenbach’s research project has the goal of improving our understanding of the ways that critical illness can affect brain function in older individuals, and will help direct future studies to minimize the risk of this problem.
Assistant Professor of Emergency Medicine
University of Colorado Denver
Vitamin D and Immunosenescence in Older Long-Term Care Residents
Infections are common in older adults resulting in increased healthcare utilization and morbidity. As life expectancy increases, the increased incidence and severity of infection associated with aging has become a critical public health issue. Infection impacts the function, independence, and survival of older adults, and is a major contributor to healthcare utilization and costs. Vaccines improve host defense against pathogens and reduce the incidence, severity, and duration of common infections. However, the immune response to infectious pathogens and effectiveness of vaccines decline with advancing age. Dr. Ginde's research is investigating the role of clinical interventions, particularly vitamin D, in improving the immune response to infection and vaccines, with the goal of ultimately reducing the incidence and severity of infection in older adults.
Assistant Professor of Medicine in Residence
University of California, San Francisco
A Multidimensional Approach to Urogenital Aging in Older Women
Between one quarter and one half of older women develop symptoms and complications of urogenital aging that interfere with their activities, functioning, or quality of life. While previous research on urogenital aging has focused almost exclusively on the role of estrogen deficiency, variations in estrogen levels do not adequately explain differences in the severity of women's urogenital symptoms, their impact on quality of life, or their responsiveness to treatment. For this award, Dr. Huang has incorporated multiple urogenital and geriatric measures into a cohort of ethnically-diverse, middle-aged and older women in California. Using these measures, she will examine how older age, greater comorbidity, functional decline, and frailty influence the severity, impact, and utilization of treatments for urogenital symptoms in postmenopausal women across the age spectrum. The proposed work has the potential to identify as-yet unrecognized geriatric factors that can influence women's urogenital function and lead to new strategies for preventing and treating urogenital aging symptoms in women.
Assistant Professor of Neurology
University of Utah
Cortical Complexity Changes in Normal Aging and Alzheimer's Disease
The purpose of Dr. King's Beeson research is to develop new quantitative methods to be used to measure changes in the size and shape complexity of the cerebral cortex as derived from magnetic resonance images of the brain. It is important to understand the extent and distribution of size and shape changes in the brain that occur during healthy aging because many of these changes are not associated with cognitive dysfunction. Using measures of cortical shape complexity as a novel method to assess brain aging may improve the ability of doctors to distinguish normal aging from early neurodegenerative disease, and provide a method of detecting the earliest changes of Alzheimer's disease before other symptoms appear.
Assistant Professor of Hematology and Oncology
Wake Forest University Health Services
Minimizing Physical Function Decline in Older Adults Receiving Chemotherapy
Older adults represented more than half of the over 1.5 million new cancer cases estimated in 2010. While chemotherapy is offered increasingly as part of cancer treatment to older adults, it is known that chemotherapy side effects increase significantly with age. These side effects can result in disability that compromises quality of life, limits treatment options, and contributes to the social and economic burden of managing chronic disease. Dr. Klepin is developing a program of physical activity to be used during cancer treatment designed to minimize these negative side effects, thus maximizing functional independence for older cancer survivors. Her study will focus on older adults receiving chemotherapy for acute leukemia and measure the feasibility and beneficial impact of an exercise program on physical function and quality of life during treatment.
Assistant Professor of Medicine
University of California, San Francisco
Individualizing Treatment for Nursing Home Residents with Diabetes Mellitus
Diabetes mellitus (DM) is becoming increasingly common in the nursing home population. However, there is great uncertainty about the optimal level of blood sugar control for nursing home residents with DM. Dr. Lee will determine the current practices for blood sugar control in a national sample of veterans affairs (VA) nursing homes, as well as whether the level of blood sugar control is associated with geriatric outcomes such as incontinence and falls. He will explore the goals of treatment and preferences of individual residents regarding treatments (e.g. insulin) and outcomes. By determining the current practices and the relationship between the level of blood sugar control and geriatric outcomes, he will help patients and clinicians make individualized decisions about diabetes care.
Assistant Professor of Medicine
University of Colorado Denver
Implanted Defibrillators and Older Adults: A Model of Decision and Technologies
Patients are often not adequately informed when receiving medical care, which can lead to unwanted treatments or unexpected consequences. This problem is heightened for older adults, who are more likely to be cognitively impaired, have lower health literacy, or be passive in their decision making. With the increasing availability of new medical technologies, which involve important health and quality of life trade-offs, empowering patients and families to make educated decisions about medical technologies is an important component of patient-centered care. Dr. Matlock will attempt to provide real world estimates of the risks and benefits, as well as to improve our understanding of older adults' values around one common technology, Implantable Cardioverter-Defibrillators (ICD). Based on his discoveries, Dr. Matlock will develop and test a web based ICD decision aid for patients and their physicians.
Staff Scientist and Assistant Adjunct Professor
J. David Gladstone Institutes/UCSF
Mechanisms and Treatment of Network Dysfunction in Alzheimer's Disease
Alzheimer's disease (AD) and other age-related neurodegenerative disorders are major sources of disease and death for older adults. AD is associated with an increased incidence of seizures as well as cognitive decline. These seizures, as well as over-excitation of the neurons not severe enough to create noticeable symptoms, may contribute to cognitive deficits. Dr. Vossel will investigate strategies to counter over-excitation of neurons and seizures in AD. Two components of the brain deposits characteristic of Alzheimer's disease, amyloid-β (Aβ) and tau protein, disrupt the function of cellular components that would normally regulate neural activity. Dr. Vossel will attempt to determine the mechanisms by which reducing tau protects against seizures in mouse models of AD. He will also attempt to identify people in the early stages of AD who could benefit from tau-targeted strategies or existing antiepileptic drugs.