Awardees By Year
2012 Grantee Summaries
Determining and manipulating age-dependent changes in myocardial stiffness, in vivo
A common characteristic of cardiac failure in old age is loss of elasticity that allows the heart to properly fill with blood in anticipation of its next contraction. Understanding the genetics behind age-related stiffening of heart muscle is the goal of Dr. Cammarato’s innovative research. Using live video and atomic force microscopy and fruit flies, he will perform the first direct analysis of age-associated mechanical changes in the hearts of living animals. With measurements of age-associated changes in heart muscle stiffness in hand, Dr. Cammarato will turn his attention to the genes that modulate the physiological properties of aging heart muscle. His hope is to identify potential targets for treating and possibly preventing the stiffening of heart muscle over time, thereby by mitigating one risk factor for heart failure.
Inactive older adults: determining the role of system A and L transporters underlying an amplified anabolic response in muscle
Regaining muscle strength after an extended period of inactivity requires both exercise and proper nourishment. When the elderly require long periods of bed rest due to illness or injury, they experience faster deterioration of muscle and longer periods of recovery. In previous studies, Dr. Drummond has observed that the combination of age and inactivity can result in a significant drop in the effected muscles’ ability to process the essential amino acids (EAA) necessary to rebuild atrophied muscle. In this research project, Dr. Drummond will first test a 12-wk program of intense physical activity combined with nutritional supplements using enriched EAA. His goal will be to reverse atrophied muscles’ impaired responses to EAA intake. The data from this study will be used to design follow up experiments with the overarching goal of determining how to decrease muscle atrophy among the elderly when extended bed rest is required.
Differential relationships between diabetes risk factors and brain structure and function
The inability of our body’s naturally produced insulin to regulate blood sugar levels properly is a condition known as diabetes. Risk factors for Type 2 or adult-onset diabetes include obesity and aging. Diabetes increases both the rate of mild aging-related mental decline and the risk for dementia, including Alzheimer’s disease. However, not all people with diabetes or diabetes risk factors experience greater than normal mental decline. Dr. Hugenschmidt’s study will seek to determine the diabetes risk factors that most reliably predict greater risk of developing conditions like Alzheimer’s disease. Her team will add data on mental performance, brain structure and brain connectivity to existing data on reversing risk factors for diabetes from an ongoing weight-loss trial in older adults who were identified as at risk of developing diabetes. Understanding the biological mechanisms linking diabetes with dementia will help develop new and better treatment and prevention strategies.
Targeting CD137 to enhance RSV peptide vaccine efficacy in aged mice
Respiratory Syncytial Virus (RSV) causes about 12,000 deaths per year in the elderly. It is responsible for 11% of hospitalizations for pneumonia. Despite numerous efforts, no effective vaccine for RSV has been developed. Dr. Lee’s team found that impaired RSV-specific CD8 T cells and delayed RSV clearance in aged mice compared to young mice. Her team created a peptide vaccine approach called TriVax, which generated robust CD8 T cell response and complete protection against RSV infection in young mice but not in aged mice. Her current proposal will define whether co-administration with an agonistic antibody (CD137) may rescue TriVax efficacy to enhance CDB T cell response in aged mice. Her goals are to better understand the underlying mechanisms that lead to the decline of the immune system as we age and to establish a basis for a novel vaccine strategy against RSV in the elderly.
Multimodal neuroimaging biomarkers of caloric restriction protective effects in aging mice
Tests with a wide range of animals have shown that a diet restricting calorie intake while ensuring healthy nutrition slows the age-related decline of a variety of physiological functions. But the effect of caloric restriction (CR) on brain metabolism and cognitive function has not been widely studied. Dr. Lin proposes an innovative research model designed to document the effects of CR on the living brain. She will use non-invasive neuroimaging methods (e.g. MRI, PET) to confirm the protective effects of CR on brain metabolism as the brain ages and to explore the physiological effects on the brain’s mitochondria. This also will be the first study to investigate the correlation between memory and spatial information processing and the brain imaging results of her CR mice. Dr. Lin hopes her non-destructive research approach will help determine if CR is a viable approach to preserving the integrity of human brain function as we age.
Zinc homeostasis dysfunction in vascular aging
Cardiovascular diseases (CVD) are among the leading causes of death worldwide. Aging is associated with many physiological changes that can cause CVD. For example, increased inflammation in artery walls promotes atherosclerosis. This heightened inflammation response has been tied to changes in the function of aging vascular smooth muscle cells (VSMC). Dr. Salazar seeks a better understanding of the molecular mechanisms that lead to the breakdown of functions at the cellular level. In previous research, she has found that zinc deficiency is linked with an increased risk of CVD. How zinc levels contribute has not yet been explored. Dr. Salazar’s new research will use zinc-deficient and zinc-enhanced diets to test the effects on VSMC. The goal of her work is to provide insight to possible nutritional approaches to the lowering and/or treatment of age-related risk of CVD.
ERK5/KLF4 signaling and glia-neuron interaction
To date, most research on the causes of diseases characterized by the degeneration of neurons has focused on the breakdown of functions within the neurons. Much less research has been done on the various types of non-nerve pulse carrying brain cells called glia. Dr. Su’s work will focus on communication between neurons and glia. Research has already shown the steroid hormone progesterone can protect cells against agents that typically cause cell death. But that same protection is not as robust when neuron- or glia-enriched cultures are tested separately. This suggests that neuron-glia interaction may be involved in assuring the full beneficial effects of progesterone. Dr. Su’s work will focus on the signaling pathway between glia and neurons and its impact on progesterone-induced cell protection. This work could lead to novel strategies for preventing and/or treating neurodegenerative disorders associated with aging.
Determining neurogenesis-induced neural circuits in the aged mice
The brain’s plasticity to continuously generate and incorporate new brain cells into its circuitry, particularly in the hippocampus, plays a key role in our ability to think, learn, remember and express emotion. Creation of new brain cells declines as we age, leading to the mental deficiencies associated with growing older. Dr. Suh has developed a unique tracing system that allows his team to follow new circuit development in the adult hippocampus. His study will identify circuits in the brains of mice that support creation of new memory and learning ability, which seem to falter with age. His team will then test whether there is a difference in how these circuits perform in sedentary versus running mice. Dr. Suh’s study will provide a better understanding of the brain circuits that are disrupted as we age and provide insight to whether voluntary exercise may be a way to slow or even reverse aging-related loss of the circuit formation.
The role of mTOR in the development of cardiac hypertrophy during aging
Mammalian target of rapamycin, or mTOR, is an enzyme that regulates cell growth, movement and survival. Regulation of mTOR signaling has been shown to play an important role in the effects of aging at the cellular level. With 90% of all heart failure deaths occurring after age 70, Dr. Zhang is particularly interested in the role of mTOR on cardiac aging and the development of cardiovascular diseases (CVD). His preliminary studies have shown that mTOR signaling increases with age. He has also shown that suppressing mTOR signaling reduces the unhealthy enlargement of the ventricles of the heart, which is often characteristic of heart failure. With this new research, Dr. Zhang will further test his hypothesis that mTOR plays an important role in cardiac function over time by inhibiting mTOR signaling in his mouse model at different ages. His findings could lead to preventive therapies for CVD among the elderly.
Mitochondrial isocitrate dehydrogenase and age-related hearing loss
Age-related hearing loss (AHL) is a common condition among people 65 years and older. Caloric restriction (CR), the reducing of food intake without malnutrition, has been shown to increase longevity and delay the progression of age-associated diseases, including AHL. CR is thought to slow the development of AHL by reducing the imbalance between the number of oxygen-containing molecules in the body and the body’s ability to regulate them, and/or by enhancing mitochondrial antioxidant defenses in the inner ear. Dr. Someya’s research to date has shown that CR slows AHL in part by increasing the activity of a specific mitochondrial enzyme that is critical to the ear’s biochemical defense mechanisms. The aim of this project is to determine whether this enzyme helps slow the progression of AHL in mice by enhancing the mitochondrial antioxidant defenses under CR conditions. The results of this project will provide an enhanced understanding of the fundamental molecular mechanisms underlying AHL.
The cell biology of protein aggregation in a C. elegans Alzheimer Model
Our body has a highly specialized quality control system for balancing the production of amino acid chains, folding these chains into various functional proteins, and destroying misfolded proteins. If the system cannot fix or clear misfolded proteins, they tend to aggregate in cells to form structures called inclusion bodies. Alzheimer’s disease has a direct link to the failure of cells to properly manage protein folding. However, little is known about the role inclusions play in aggregation toxicity. Dr. Kaganovich believes the starting point for uncovering the origins of AD pathology must be a thorough understanding of the general cell biological function of inclusions, and their potential role in modulating the toxic consequences of protein aggregation. His previous research has shed light on the possibility that aggregation and inclusions formation is not always toxic, and might sometimes be part of a natural protective process. His new study will move his research from an abstracted cell culture model into the roundworm (C. elegans) enabling him to explore the cell biology of protein aggregation in the context of a living, aging organism, and thereby provide insights to therapeutic targets when protein quality control begins to break down.
Technion — Israel Institute of Technology
Longitudinal functional characterization of neurodegeneration induced by Cdk5 aberrant activation using optogenetic fMRI
Early identification of alterations in brain function due to the development of Alzheimer’s disease could allow for the development of therapies that slow or reverse the disease even before its debilitating symptoms begin to appear. Leveraging recent advances in the use of optogenetic functional magnetic resonance imaging (termed 'opto-fMRI') to control brain cell activity in living animals, Dr. Kahn will use repeated whole-brain functional imaging sessions on the same animal conducted before the onset of and during the degenerative process. He aims to identify physiological changes that precede the obvious structural and behavioral changes that result from the progression of the disease. His research is expected to contribute to our understanding of brain-wide structural and functional alterations during the degeneration of brain cells, and potentially reveal novel markers of degeneration that precede the characteristic symptoms of AD.
Assistant Professor of Pathology
Regulation of dendrite dynamics and amyloidogeneic APP processing by beclin 1
Among the delicately balanced and highly regulated processes that affect the health of brain cells is the cleaning up of waste materials and cellular debris. One of the characteristics of Alzheimer’s disease is the accumulation of amyloid beta (AB) into plaques that destroy neurons. Research into why toxic levels of AB accumulate as AD progresses has noted that a protein critical to the process of clearing out cellular debris, beclin 1, is reduced in AD patients. Dr. Plowey’s research will focus on developing a better understanding of the relationship between beclin-1 and the increase and/or decrease of amyloid beta levels. He will examine the impact of beclin-1 on the creation of AB from the amyloid precursor protein in the hope of determining if maintaining optimal beclin-1 levels could be a therapeutic target for AD patients.
PGC-1alpha as a neuron protector in Alzheimer’s disease
In examining the mitochondrial network of Alzheimer’s disease affected cells in both animal and human brains, Dr. Wang and his colleagues have observed that the network is characterized by fragmented mitochondria (energy factories of cells) and abnormal distribution of mitochondria. He believes this disrupted network causes mitochondrial dysfunction and likely contributes to dysfunction in the affected brain cells. Dr. Wang’s preliminary studies demonstrated that over-expression of a key gene-regulating protein, PGC-1α, increases mitochondrial length and movement. His research suggested that the creation and subsequent activity of mitochondria are likely related and that it is possible to improve mitochondrial activity through manipulation of its creation. His new study will be the first to assess whether PGC-1α is a valid therapeutic target to improve mitochondrial and neuronal function in AD. If successful, it will open the new avenue for mitochondria-targeted research and drug development for delaying aging and the onset of aging-associated neurological diseases.
Role of microRNA 146b in regulating macrophage senescence
Inflammation is an important protective mechanism our bodies use to repair injury and initiate healing. However, chronic cellular inflammation and that caused by the improperly regulated release of inflammatory substances is a common characteristic of many age-related diseases, ranging from blinding eye diseases to cancers. Dr. Apte’s research has focused on inflammation mediators released by specific cells called macrophages. Macrophage mediated inflammation has been implicated in many disorders associated with aging. The precise mechanisms that cause the age-related changes in the cells’ activities are not known. What Dr. Rajendra’s team has learned is that decreased levels of a specific micro ribonucleic acid (miR-146b) is related to dysfunction in macrophages. His new research will focus on how miR-146 and its specific gene targets regulate macrophage activity with the goal of determining if enhancing miR-146 levels is a viable target for preventive treatment of age-related disorders.
Thymic preservation and immune function
The thymus is a highly specialized organ of the immune system. It is integral to the creation of T-cells that attack and destroy tumors and disease-causing pathogens. The thymus is largest and most active in the womb and at birth. Thereafter, the thymus begins to shrink. The slow, progressive natural degeneration of the thymus with age is thought to be a reason why the elderly are more susceptible to infection. Rejuvenation of the aged thymus has been argued as a way to restore immunity in the elderly. Dr. de Vallejo's team has shown that mice deficient in specific plasma protein (PAPPA) are long-lived animals that retain a robust thymus throughout life. His new research will examine factors underlying preservation of the thymus and evaluate if the thymic preservation confers immune protection in old PAPPA-knockout mice. His findings may lead to strategies for preserving or prolonging thymus function in order to promote healthier aging.
INK-ER-Cre mice: a novel tool for uncovering how senescent cells cause age-related dysfunction
Senescent cells are old or damaged cells that have stopped dividing. Though they no longer behave like healthy cells, they continue to secrete proteins and enzymes into the body. Senescent cell secretions include proteins associated with inflammation in various tissues of the body. This inflammation is characteristic of many age-related diseases, such as dementia, depression, atherosclerosis, cancers and diabetes. Dr. Kirkland’s research on mice in collaboration with Drs. Baker, Tchkonia, van Deursen, and others at Mayo has already shown that removing senescent cells has a dramatic effect. It delays deterioration of muscle tissue and strength, slows the accumulation of fat under the skin and even wards of cataracts. Dr. Kirkland and his team will use a new mouse model to test their hypothesis that preventing the release of senescent cell secretions may delay or even prevent some age-related dysfunction. If successful, their research could lead to the development of therapies targeted specifically at senescent cell activity.
A novel protein disaggregase – from molecular mechanisms to novel cures
Alzheimer’s, Parkinson’s and Huntington’s are all examples of diseases characterized by the aggregation of proteins that would normally be removed by the body’s regulatory system. As they accumulate, these protein aggregates become toxic, choking off normal brain cell function. Understanding the molecular mechanisms of protein aggregation is critical to developing potential therapies. Molecular chaperones are proteins that assist in the creation of larger molecular structures without becoming part of those completed structures. Dr. Shan’s laboratory has discovered a novel molecular chaperone that reverses protein aggregation. Her team’s new research will uncover the molecular mechanisms by which this chaperone recognizes and disrupts protein aggregates. They will then engineer chaperones to remove protein aggregates associated with aging, thereby providing the foundation of a new approach to treating age-related protein aggregation.
Vesicle trafficking defects & mitochondrial dysfunction related to α-syn toxicity
Neurological disorders characterized by insoluble deposits of alpha-synuclein protein, such as Parkinson’s disease and dementia with Lewy bodies (DLB), are second only to Alzheimer’s disease in frequency of occurrence among the elderly. The causes of these diseases remain a mystery; however, genetic mutations and abnormal folding of α-synuclein are clearly part of the process. Dr. Auluck’s research will focus on two basic cellular functions that seem to be disrupted as a consequence of α-synuclein toxicity. First he’ll look at defects in the transporting of proteins between locations in the cell. He will then examine dysfunction in mitochondria that appears to be a consequence of a severe increase in accumulation α-synuclein and how these defects predispose affected brain cells to degeneration. His experiments will test the hypothesis that α-synuclein induced transport defects precede and cause mitochondrial dysfunction. The results will also deepen understanding of the basic cellular causes of α-synuclein associated diseases.
Neural correlates of impaired financial and health-care decision-making in old age
Elderly adults are constantly faced with important decisions, such as financial and health-care issues. Recent studies suggest decision-making abilities can become significantly impaired with age. Relatively little is known about the correlation between brain measures and impaired decision-making in older adults. Dr. Han will apply his expertise in neuroimaging to a comprehensive, multi-disiciplinary study of non-demented older adults that will integrate multi-level imaging methods sensitive to brain structure and function. His work will also connect with recent approaches to studying how cognitive functions and memory combine with personality traits to form different styles of decision-making. The study and its findings will inform a comprehensive training program in neuroimaging, decision-making, bioethics, geriatrics, neuroepidemiology, biostatistics, and leadership skill development.
Improving care for older adults with serious illness
Advancing the quality and value of health care for seriously ill older adults is becoming an increasingly important social issue as the United States’ elderly population grows. Understanding what factors contribute to unnecessary or unwanted hospitalizations among older adults is essential for developing successful new models of care that focus on quality of life and patient satisfaction. Dr. Kelley’s study will evaluate factors, ranging from family support and health conditions to regional medical resources and patterns of care, that may influence treatment. She will then work with seriously ill people at risk of high-cost hospital-based care to identify “triggers” of unnecessary and/or undesirable hospitalizations and the barriers to avoiding them. She will learn from patients and families what factors lead to excess hospitalizations and how these barriers might be overcome. Her goals are to create a patient-centered approach that reduces unnecessary hospitalizations among seriously ill older adults and to translate the work into effective health care policies and clinical programs that better align treatments with patient preferences.
Hippocampal structure and function in cognitive impairment
Though a great deal of research is being done on the causes and potential treatments of Alzheimer’s disease, Dr. Kerchner sees a critical need to identify biological indicators of AD at the earliest signs of memory loss. Such biomarkers could help with the timely delivery of disease-modifying therapies to minimally affected patients who have the greatest chance of curtailing the disease’s deadly progression. Neuroimaging holds great promise for identifying biomarkers, but conventional technologies are insensitive to early manifestations of the disease. Dr. Kerchner’s research will apply two complementary, high-resolution advanced imaging technologies to a study of the structural and functional changes in the hippocampus that correlate to memory loss. The ultimate goal of the study is to identify the baseline structural and functional imaging metrics that predict subsequent cognitive decline and may prove to be targets for proactive therapies.
Health IT decision support to improve medication management safety and quality
Patients dealing with multiple chronic health issues are frequently prescribed several medications. Managing multiple medications means dealing with issues related to drug interactions, inappropriate medications, and poor compliance with doctors’ prescribed use. These issues are further complicated among elderly patients who often have problems with memory and decision-making. Health information technology (HIT) holds great potential for improving the safety and quality of medication management. Dr. Moreno’s study in partnership with a rural community health center will examine medication practices among patients 60 and older. He will use feedback from physicians, nurses, pharmacists, and patients to help develop a prototype medication management application. His work will ensure any technology developed is widely accepted by the end-users and addresses the most important barriers to safe prescribing and compliance among older adults with chronic conditions.
Age associated defects in localization and trafficking of toll-like receptor 1
Dr. Panda’s research focuses on defects of the innate immunity arm in older adults. Aging is associated with a progressive decline in immune function (immunosenescence) resulting in increased susceptibility to viral and bacterial infections and decreased response to vaccines. Toll-like receptors (TLRs) are pattern recognition receptors that recognize conserved molecular patterns on microbes and are key to triggering antimicrobial host defense responses. Deficiencies in human TLR signaling lead to increased severity of several diseases, including sepsis, immunodeficiencies, atherosclerosis and asthma. Dendritic cells (DCs) are the major antigen presenting cells responsible for initiating an immune response. However, DC functions in aging have not been studied in detail. Dr. Panda recently demonstrated a generalized defect in TLR function in DCs from older individuals. As a Beeson Scholar he will study the mechanism of decreased TLR function in dendritic cells of older adults. His preliminary studies indicate a potential role of the chaperone Protein Associated with Toll-like receptor 4 (PRAT4A) in mediating the age-associated defects observed in TLR expression. He hypothesizes that the expression of PRAT4A is decreased with aging and therefore is a potential target for therapeutic intervention. In addition he will study underlying mechanisms of diminished PRAT4A and TLR1 expression in older adults. Ultimately, he hopes that his work will help explain the deterioration of immunity seen in older adults, and aid in the rational development of novel treatments and vaccines geared specifically towards older adults. “My research will benefit almost two million older adults hospitalized with an infectious disease each year in the United States.”
Effects of aerobic exercise on EPCs and vascular dysfunction in aging and T2DM
There is evidence to suggest that cardiovascular complications among the elderly and among people with adult-onset diabetes (Type 2) may in part be due to dysfunction in cells that are critical to the growth and repair of blood vessels. These cells, known as EPCs, appear to decrease in number and function in the circulatory system as we age and/or develop diabetes. Dr. Prior has done preliminary work that suggests aerobic exercise training may increase EPC and vascular function in diabetics, but that the positive effects of exercise may be reduced as we age. His new study will further test his hypotheses that reduced EPC function adversely affects vascular function in type 2 diabetics, and that there is an age-related difference in the ability of aerobic exercise programs to improve EPC function. The identification of the mechanisms and effects of EPC and vascular dysfunction could identify targets for therapeutic interventions to reduce risk for cardiovascular complications, especially in people over 65 years of age.
Late life disability: epidemiology, symptoms, quality of life
The number of elderly people in the United States living with some form of disability will increase dramatically over the next several decades. Living with significant disability has major potential impacts on quality of life, caregiver burden, and the use of healthcare and social services. Little research has been done on how long elders with various disabilities can expect to live. This information is important from the perspectives of patients, caregivers, service providers and policymakers. Furthermore, quality of life concerns of elders with late life disability have not been well described. Dr. Smith’s research will provide the first nationally representative estimates of the amount of time elders spend in disabled states prior to death, and examine how key demographic characteristics impact life expectancy. In addition, he will test and refine a conceptual model of quality of life for disabled elders and pilot a longitudinal study of factors influencing quality of life over time, including end-of-life outcomes.
Ashley M. Fortress, PhD
Postdoctoral Research Associate
University of Wisconsin-Milwaukee
Exploring the epigenetic mechanisms behind age-related cognitive impairment following acute 17beta-Estradiol administration in ovariectomized mice
Steep drops in estrogen levels in menopausal women have been linked to accelerated loss of mental abilities, particularly memory. Data from both rodent models and women suggest that treatment with the potent estrogen 17B-estradiol (E2) can reduce age-related memory decline. However, estrogen replacement therapy carries with it increased risk of heart disease, stroke and cancer. Furthermore, estrogen replacement does not have the same memory enhancing benefits for older, post-menopausal women. Dr. Fortress believes there may be a way to develop new treatments that mimic the beneficial effects of E2 replacement without the health risks. Her team’s work focuses on pinpointing critical biochemical mechanisms in the brain through which E2 enhances memory in aging female mice. Her research will provide a better understanding of how estrogen loss affects cognitive function. Her findings could lead to novel therapies that reduce health risks for menopausal women and extend therapeutic benefits to older women as well.
Engineering gene networks to halt developmental drift and slow aging in C. elegans
Research has provided many hypotheses for how we age, but there is still a great deal of uncertainty as to the root cause of the physiological processes associated with growing older. Recent studies have suggested a cause in which the regulatory system that controls how gene networks express themselves begins to break down. Researchers hypothesize that misregulation of gene expression leads to physiological changes, some of which we chalk up to “old age” while others manifest as diseases. The aim of Dr. Friedland’s project is to test this hypothesis by engineering enhanced gene network regulation in roundworms. Building on the successes of the past decade’s work in synthetic biology, Dr. Friedland’s team will construct synthetic gene networks to sense the expression levels of genes that control the expression of thousands of other genes. Their goal will be to maintain expression levels characteristic of the young adult roundworm. If changes in gene expression is causally connected to aging, such engineering should result in animals that live longer and stay healthy for longer.
Single-cell analysis of the aging methylome
Epigenetics refers to functionally relevant changes to an organism’s DNA that do not involve a change in the structural units that make up the genetic sequence. Dr. Gravina’s research project is based on the hypothesis that epigenetic information is less stable than an organism’s corresponding DNA sequence and is, therefore, a more likely candidate for errors. These errors can lead to what researchers have observed as an age-related drift away from the proper regulation of how a healthy body’s genetic information is expressed. Dr. Gravina sees one common epigenetic process, DNA methylation - a DNA modification that helps determine which genes are turned on and off - as a prime target for studying gene regulatory drift. Working with a method she developed for measuring DNA methylation patterns in individual cells, her project will test the hypothesis that random DNA methylation changes accumulate in the aging heart and contribute to the functional decline of cells. This decline at the cellular level may give rise to classic signs of aging.
Kristin Gribble, PhD
Josephine Bay Paul Center for Comparative Molecular Biology and Evolution, Marine Biological Laboratory
A comparative ecological and evolutionary investigation of the molecular mechanisms of lifespan extensions by caloric restriction
While caloric restriction (CR) is the only means known to increase longevity in a wide variety of organisms, there is no consensus on the molecular and genetic mechanisms controlling this phenomenon. Relatively little experimental testing of competing evolutionary theories has been done; there remains a need to connect the genetic mechanism of the response to CR to an evolutionary framework of aging. Dr. Gribble’s project will characterize and compare the lifespan and reproductive fitness responses to CR in multiple populations of closely related microscopic aquatic invertebrates with different CR-related traits. By mapping the ecological variables of their evolutionary environment with response to CR for each population she will be able to study various theories of aging. Through comparison of gene expression differences between the populations, her work will help identify and characterize genes involved in longevity in response to CR and confirm or refute her hypothesis of the evolutionary origin of CR responses. Her results will also help in the prediction of outcomes and side effects of CR-related therapies.
Antagonistic pleiotropy of IGF/insulin signaling and the control of metabolic homeostasis
Insulin is a critical regulator and coordinator of metabolic function. Age-related metabolic diseases, such as diabetes, are associated with a condition called insulin resistance in which the body’s natural response to insulin is impaired in select tissues. Strikingly, research has also shown that reducing insulin responses in many tissues can actually extend the lifespan of those tissues and the whole organism. This contradiction highlights the need for a better understanding of the physiological consequences of decreased insulin activity. Dr. Karpac’s study uses a fruit fly model to characterize these consequences through genetic analysis. His previous work has established both positive and negative roles for reducing insulin activity in cells of the fly’s intestine. This project will test the hypothesis that age-related changes in insulin activity in differentiated cells of the gut cause metabolic imbalances and limit lifespan. He expects the findings obtained will provide greater insight to the causes and consequences of age-related metabolic imbalances.
The role of satellite cells in aged-skeletal muscle maintenance and hypertrophy
Satellite cells are a type of stem cell involved in the normal growth of muscle, as well as regeneration of muscle tissue following injury or disease. Loss of muscle mass, strength and function is common among the elderly and significantly impacts quality of life. Also, strengthening exercises to offset progressive weakening has been shown to be less effective as we age. It has been proposed but not proven that over time the impairment and/or loss of muscle satellite cells contributes to the weakening of muscles. Dr. Lee’s team has devised a novel genetic research approach using two established mouse strains that combine to provide optimal study of satellite cells across their lifespan. Their project will be the first test specifically of the role of satellite cells in the maintenance of muscle tissue as it ages. They will also examine the effects of age on the muscle’s response to strengthening stimuli. Understanding the roles of satellite cells in aged-skeletal muscle will directly impact future research focused on developing therapies and strategies to prevent age-associated muscle loss.
Investigating the role of the hypoxic pathway in aging in C. elegans
Hypoxia is a condition that results when an organism is deprived of adequate supplies of oxygen. Oxygen deprivation is generally bad for one’s wellbeing. However, Dr. Leiser’s lab recently published the first of several reports on a new genetic pathway, dubbed the hypoxic response pathway, in which they reveal that a protein important to survival in low oxygen environments has the ability to increase longevity in roundworms. Conversely, a mutation in one of the proteins responsible for regulating this pathway causes von Hippel-Lindau disease, a well-known disease that can lead to vision problems, strokes, heart attacks and cardiovascular disease. Dr. Leiser seeks to translate what is known about this pathway into human aging with a research plan focused on the tissues and downstream components involved in increasing roundworm longevity. Armed with a better understand how hypoxic response is able to delay aging in worms, he hopes to discover a basis for studying how stress response pathways like hypoxic response may contribute to improving the lifespan and healthspan of higher organisms.
Characterization of novel small molecule modulators of lifespan
Dr. Lucanic’s team has carried out high-throughput screening of over 30,000 diverse synthetic compounds to identify compounds that can improve longevity of the roundworm. His latest research will follow-up on approximately 50 as yet uncharacterized compounds identified as extending lifespan. He will also expand on his preliminary studies of a group of particularly potent and structurally related compounds that seems to mimic dietary restriction. The compounds appear to extend lifespan in the worm by hindering the animal’s ability to detect its bacterial food, thereby mimicking a state of low nutrients. Dr. Lucanic will study the effects of these compounds on the neuronal system that controls feeding behavior and characterize how that system promotes the responses that influence lifespan. His hope is that his deeper characterization of various life-extending compounds will provide a basis for the development of new pharmacological treatments of age-related diseases.
The genomic basis of increased high-density lipoprotein cholesterol (HDL) in humans with exceptional longevity
Dr. Milman’s project focuses on a unique population of centenarians and their families who are generally free of age-related diseases. Healthy longevity runs in most of these families, suggesting a heritable basis for this phenomenon. One trait associated with the health of this population is elevated high-density lipoprotein (HDL) cholesterol. Significant evidence exists that higher HDL cholesterol levels are associated with decreased risk of common age-related diseases, like diabetes, cardiovascular disease and Alzheimer’s. Dr. Milman’s team will do Genome-Wide Association Studies (GWAS) to discover genes associated with both high HDL levels and longevity. They will also use data from longevity Epigenome-Wide Association Studies (EWAS) to study the effects of epigenetic modifications on the function of these genes and the associated HDL levels. Finally, they will attempt to validate their findings by studying children of parents with exceptional longevity.
Functional assessment of Chaperone Mediated Autophagy during aging in Drosophila
As we age, damaged byproducts of biological functions accumulate in our cells. When accumulations reach toxic levels it leads to age-related disease and debility. Autophagy is a process that keeps cells healthy by cleaning out toxic byproducts and supplies “fuel” during stress. Autophagy activity is known to decrease with age. Dr. Mukherjee and the Jenny lab team will explore the possible contribution of one of the autophagy pathways, known as Chaperone Mediated Autophagy (CMA), or a CMA-related process, in delaying the damaging effects of aging and improving longevity. Due to its close genetic relationship to humans, they will use the fruit fly as their model organism. The availability of a wide variety of elegant genetic tools, a short generation time and a very well conserved basic autophagy machinery make flies an excellent model system for studying the effects of different genetic processes on aging. Dr. Mukherjee will characterize a CMA‐like process in Drosophila and follow its progression over the lifespan of flies. Their work will be helpful for identification of novel components of the pathway and understanding their potential significance in preventing age-related disorders and diseases in humans.
Factors responsible for age-associated impairment in maturation of NK cells leading to decreased resistance to an acute viral disease
Among the many changes our bodies go through as we age is the diminishing ability of our immune system to fight off disease. Natural killer (NK) cells are bone marrow (BM) derived immune cells crucial for defense against various infections and cancers. Dr. Nair’s team recently showed that aged mice have lower numbers of mature NK cells and this hampers the ability of their immune system to control the early spread of mousepox, a virus that is the mouse equivalent of smallpox. The result is much higher levels of infection and death in older mice. The goal of Dr. Nair’s project is to determine the mechanisms responsible for the loss of NK cell function during aging. In particular, she will determine whether the lower number of mature NK cells is the result of something happening inside the cell or outside. Results from the study will include a better understanding of how immune function is lost in the elderly and how we can prevent or reverse this loss in order to enhance the body’s defenses against infection and cancerous cells.
Epigenetic mechanisms of longevity determination in C. elegans
The lifespan of an organism is determined by how the information coded into its genes interacts with its environment. Proteins called histones package our genetic information, or genome, into structural units and play a major role in how the genes are expressed in the body. In the course of doing their work, these proteins are modified in ways that regulate other biochemical interactions. Appropriate histone modifications are critical for the proper functioning of our genes. Dr. Pu’s team will use state-of-the-art technology to monitor the whole genome pattern of several histone modifications through various stages of aging in normal roundworms and in worms whose genes have been mutated to increase longevity. Their study will provide the first comprehensive analysis of age-dependent differences in the global histone modification pattern in the worm. Since many findings from work with the roundworm have informed how longevity is affected in other organisms, Dr. Pu’s work will be broadly relevant to many species and the results useful to the entire aging research community.
Characterization of the UPRer as a cell non-autonomous regulator of age-dependent stress resistance and longevity
As we age, proteins damaged in the course of doing their work begin to accumulate rather than being detected and cleared by our body's complex cell cleaning system. This accumulation can become toxic and lead to various age-related illnesses. Working with roundworm models, Dr. Taylor and her colleagues have discovered that the mechanism that monitors damaged proteins in an area around the nucleus of cells cannot be activated after early adulthood. When the team genetically restored the mechanism in neurons of older worms, the worms were more resistant to stresses that cause protein damage and lived longer under normal conditions. Surprisingly, reactivation in neurons also activated the mechanism in the intestine, suggesting that cells of the nervous system can communicate with intestinal cells to coordinate response to protein damage. Dr. Taylor now aims to determine which neurons activate the mechanism in the intestine, identify the molecule that transmits the signal to the intestine, and how it is released and received. Finally, they will explore how this mechanism extends lifespan.
The role of hormone signaling pathways in regulating stem cell behavior, tissue homeostasis, and longevity in Drosophila
Stem cells are essential for maintaining tissue and organ function throughout life. Preserving stem cell function in aging organisms has been shown to extend longevity. However, research has yet to explain precisely how stem cell function affects the aging process. Dr. Wang intends to uncover how stem cell function and lifespan are coordinated by specific hormones that carry signals important to regulation of many biological processes. The proposed studies will use the fruit fly as a model system, as it has a short lifespan, tissues that are maintained by adult stem cells, and hormone signaling pathways known to regulate aging that are consistent with those of higher species. Dr. Wang will do a comprehensive survey of the activity of a subset of these pathways in stem cells and characterize their role in regulating stem cell behavior and longevity. His studies will advance understanding of the hormone signaling pathways that regulate lifespan extension, and provide new targets to combat tissue aging and the onset of age-related degenerative diseases.
Identification of age-dependent changes in the gene network regulated by the pro-longevity factor Fox03 in adult neural stem cells
Adult neural stem cells (NSCs) are critical to the production of new brain cells, including neurons. The formation of new neurons is linked to our capacity to learn and remember. The ability of NSCs to renew themselves declines sharply as we age. Dr. Webb aims to understand the molecular mechanisms underlying the age-dependent loss of NSC function. She has already identified a “longevity network” under the control of a protein (FoxO3) associated with exceptional longevity from roundworms to humans. She has also identified a link between FoxO3 and second protein (Ascl1) that is a key component in the creation of new neurons. Her new project will identify the key age-related changes in the FoxO3 longevity network, and determine the function of genes under its control. She will also determine how the FoxO3/Ascl1 gene network works during aging and whether changes in this network are related to the age-dependent decline of NSC function. Her studies may lead to treatments that help reactivate the ability of existing NSCs to renew themselves and/or facilitate stem cell therapies for age-dependent diseases.
Conserved mitochondrial derived peptides in aging and disease
Mitochondria, often referred to as “cellular power plants” because of their role in producing cellular energy, also play central roles in metabolism, production of free-radicals and cell death. All of this mitochondrial activity is relevant to the aging process. Recently, researchers at UCLA discovered humanin, a novel mitochondrial-derived peptide (MDP). Humanin has been shown to influence the survival of brain cells in Alzheimer's disease models. It is also involved in regulating insulin sensitivity. Further research in Dr. Yen’s lab has found additional MDPs that are biochemically consistent between humans and roundworms. This project will continue the team’s work with the roundworm model to examine the role of these MDPs in aging and age-associated characteristics and begin to determine the mechanism of action of these peptides. In particular, they will explore the effects of MDPs on metabolism, obesity and lifespan with the hope of gaining insight to their involvement in the fundamental aging process.