New Investigator Awards in Alzheimer's Disease
The Gilbert Foundation/AFAR Collaborative Research Awards in Alzheimer's Disease
Glenn/AFAR Breakthroughs in Gerontology (BIG) Grantees
Beeson Career Development Awards in Aging Research
 | Chad Dickey, Ph.D. |  | Ehud Cohen, Ph.D. |
Exploring the links between aging, proline cis/trans isomerization, proteotoxicity and neurodegeneration.
Although it is not entirely clear why neurodegenerative disorders emerge late in life and why distinct maladies exhibit similar emergence patterns over time, Drs. Dickey and Cohen, among others, have found that aging plays a key role in the progressive misfolding and toxic aggregation of proteins associated with the loss of structure and function of brain cells. They are particularly intrigued by the role of proteins called cyclophilins that serve as chaperones in the complex protein folding process associated with the development of age-related neurological diseases.
Drs. Dickey and Cohen hypothesize that the activity or levels of cyclophilins are diminished with age, allowing these diseases to manifest. They believe mutations in the amino acid proline, which cause neurological disorders to appear earlier in life, could provide a clue to how these diseases begin to form.
They will use dual experimental model systems, mammalian cells and the nematode C. elegans, to study the roles of cyclophilins in the correct folding and in the biological features of two proteins associated with the development of neurodegenerative diseases, presenilin-1 (PS-1) and TAU. Depending on what they discover, curbing the decline in cyclophilin activity might emerge as a novel target for the treatment of neurodegeneration.
 |  | Olivier Boutaud, Ph.D. Research Associate Professor |
Role of reactive aldehydes in amyloid induced dysfunction of synaptic transmission and initiation of neurodegeneration
Dr. Zhang has focused his research on the molecular mechanism regulating cellular communication between neurons across their synapses. He recently identified crucial changes at synaptic terminals in response to a physiological increase of molecular complexes of amyloid beta (Aβ) peptide known as Aβ oligomers. He has also shown that Aβ oligomers impair synaptic activity and initiate neuronal dysfunction, demonstrating that even a subtle but chronic surge in Aβ oligomer levels can initiate degradation of the neurons' axon and may lead to massive neurodegenration found in Alzheimer's disease.
Dr. Boutaud has been studying chemical compounds called levuglandins (LGs), which are produced as a result of a significant increase in inflammation or in chemically reactive molecules containing oxygen, a biochemical state called oxidative stress. He has demonstrated that LG reacts with Aβ and causes the formation of Aβ oligomers that are highly toxic to neurons. Dr. Boutaud also has developed small molecules that protect proteins by reacting with LG very rapidly, with the goal of using these molecules to protect the brain from age-associated injuries.
Jointly, Drs. Zhang and Boutaud will test their hypothesis that modification of Aβ by LGs promotes the formation of Aβ oligomer that is more neurotoxic than unmodified Aβ. They will characterize the effects of LGs on three forms of Aβ with an emphasis on the rate of formation of the oligomers and their molecular structures. They will also examine the effects of these modified Aβ oligomers on synaptic transmission and integrity. Successful completion of these studies should provide insight to the pathological impact of compounds like LGs on dementia, especially during the early stage of AD.
Giovanni Bosco
Associate Professor
Geisel School of Medicine at Dartmouth College
Condensins and mechanisms of cellular senescence and aging
Dr. Bosco’s team will examine the role in the cellular aging process of the molecular machines that drive the dynamic folding and unfolding of DNA within human cells. They believe some of these molecular machines are responsible for many of the abnormal DNA folding patterns seen in old and aging cells. The focus of the team’s research is activity mediated by the large protein complex condensin II. Building on their research in Drosophila, they will test three hypotheses: 1) that misregulated condensin II activity causes nuclear defects that drive age-related changes in genes; 2) that specific changes known to occur in human cell senescence require condensin II activity; 3) that over chronological time condensin activity drives progressive states of chromosome condensation, thereby hindering vital processes characteristic of healthy cells. Understanding the exact role condensin II activity plays in causing age-related defects will allow scientists to design strategies to prevent and possibly even reverse them.
Amy E. Pasquinelli, Ph.D.
Professor of Biology
University of California, San Diego
Collapse of the microRNA pathway during aging
Our genes play a large role in determining the rate at which our bodies display the effects of aging. And how our genetic make up is expressed physiologically is controlled by the inner workings of our individual cellular biology. The activities of one type of molecule called microRNA, or miRNA, control the expression of over half of our genes. Dr. Pasquinelli’s team has examined the role of the miRNA pathway specific to the aging process. They analyzed the expression and function of the key miRNA effector protein Argonaute. Dr. Pasquinelli hypothesizes that loss of Argonaute leads to widespread misregulation of gene expression, which ultimately contributes to the cellular instability that is characteristic of aging. She is seeking to determine how Argonaute’s role is diminished as we age. Her team will use this information to examine if increasing Argonate activity in aging cells can extend lifespan. Overall, the team’s aim is to uncover the molecular basis for changes in miRNA function during aging with the hope of learning if and how this regulatory process can be reestablished for the purpose of preventing age-related cellular abnormalities.
Marian (Emmy) Betz, MD, MPH
Assistant Professor
University of Colorado School of Medicine, Denver
Physician Screening of Older Drivers: Decision Rules for Geriatric Injury Prevention
Although age can affect a driver's ability to stay safe, driving can help older adults stay independent and mobile, so it is important that driving restrictions not be based on age alone. Healthcare providers are in a unique position to assess and counsel older drivers, but they need tools to help them identify which older drivers might be at risk of crashes and might benefit from further revaluation or retraining. A brief older driver assessment -- with screening and referral for those older drivers with a positive screening result -- would allow providers to identify and refer those drivers who need a comprehensive driving evaluation. This approach would avoid unfair restrictions on safe drivers and would prioritize driver evaluation resources for those most at risk and most likely to benefit from an evaluation. In preliminary research studies, Dr. Betz and her team developed a brief screening tool for healthcare providers, but further work is needed to examine the perspectives of older drivers and healthcare providers, to validate the screening tool, and to test the feasibility of a program to use the screening tool in a clinic setting. The overall objective of Dr. Betz’ Beeson award is to derive, validate and implement a brief screening tool to help healthcare providers identify older drivers who would benefit from comprehensive driver evaluation sessions, which could help older adults stay independent, mobile and safe.
Constance Fung, MD, MSHS
Assistant Clinical Professor
University of California, Los Angeles
Improving Older Adults' Decision Making for Obstructive Sleep Apnea Treatment
Untreated sleep disorders such as obstructive sleep apnea (OSA) are associated with lower health-related quality of life and increased risk of other conditions that are associated with high medical costs such as stroke, cognitive impairment, and motor vehicle crashes. Many treatment options are available, but older adults with newly diagnosed OSA may have poor knowledge of their treatment options and difficulty choosing the option that is right for them, which contributes to under-treatment. The Beeson-supported project will develop and test a decision aid for older adults who are newly diagnosed with OSA and face various treatment options. In phase 1, Dr. Fung will explore the factors that impact OSA treatment decisions among older adults, using qualitative methods and a patient survey. In phase 2, she will use these findings to develop a decision aid tailored to older adults with OSA. In phase 3, she will collect feasibility data for a future randomized controlled trial that will compare the decision aid to an attention control. The long-term goal of this award is for Dr. Fung to develop innovative strategies to help older adults choose a treatment that is right for them, based on their clinical characteristics, values and preferences.
William Hu, MD, PhD
Assistant Professor
Emory University
Early CSF detection of FTLD
Frontotemporal lobar degeneration (FTLD) is the second most common cause of dementia among subjects under the age of 65, and patients and their caregivers face unique challenges including poor judgment on the job, single parents suffering from FTLD with young children, and working spouses as caregivers. There are two main FTLD subtypes: FTLD associated with lesions immunoreactive to TDP-43 (FTLD-TDP), and FTLD associated with Tau-immunoreactive lesions (FTLD-Tau). Currently, the exact FTLD pathology cannot be confidently defined until autopsy, and as a result it is challenging to enroll the appropriate patients for substrate-specific clinical trials. There is an urgent need to identify a biomarker that can reliably predict FTLD pathology. Dr. Hu’s Beeson project aims to establish the standardized measurements of FTLD-TDP biomarkers towards translating this research panel into clinical testing, and identify biomarker changes which can be used even when symptoms are very mild. Early and accurate FTLD- TDP diagnosis will enhance future drug development and clinical trial design to alleviate the unique personal, social, and economic burden of FTLD.
Daniel Kramer, MD
Instructor in Medicine
Harvard Medical School
Patient-Center Outcomes of Implantable Defibrillator Therapy in Older Patients
More than 50,000 implantable cardioverter-defibrillators (ICDs) are placed annually in patients aged 65 and older. Demographic trends and the associated burden of heart disease will make millions more older cardiac patients eligible for these devices in the coming years. These patients face important uncertainties regarding their clinical course and health care needs after ICD implantation, which must be weighed against the risk of sudden death without the device. Two of the most challenging and costly health care transitions for older patients include nursing home (NH) and hospice admission. Which ICD recipients ultimately require NH or hospice care, and when, is entirely unknown. Additionally, their broader end-of-life experiences have not been well- characterized. Dr. Kramer’s Beeson award will address knowledge gaps related to the clinical course, health care needs, and end-of-life experiences of older ICD patients using 2 complementary approaches.
First, national databases will be used to describe the incidence and outcomes of long-term nursing home admission and hospice care following ICD placement in older patients. Second, a pilot prospective study collecting primary data from older patients with ICDs will examine outcomes related to end-of-life experiences. This work represents key steps towards better informing clinical and policy decisions regarding the use of ICDs among older patients.
Ozioma Okonkwo, PhD
Assistant Professor
University of Wisconsin-Madison
Early detection of asymptomatic middle-age adults at risk for AD
According to current projections, the number of Americans with Alzheimer's disease (AD) and other dementias will grow as the U.S. population age 65 and older continues to increase. By 2025, the number of people aged 65 and older with Alzheimer's disease is estimated to reach 7.1 million—a 40 percent increase from the 5 million aged 65 and older currently affected. To forestall this impending public health crisis, it is crucial to detect AD in its earliest, asymptomatic, stages. Dr. Okonkwo’s aims for the proposed research are: (1) specify the pattern of brain changes on magnetic resonance imaging (MRI) that is characteristic of Stage 3 preclinical AD (the stage hypothesized to impart the greatest risk of future progression to AD) , (2) prospectively assess whether cognitively-healthy individuals who harbor these characteristic brain changes exhibit a faster rate of cognitive decline when followed longitudinally, and (3) preliminarily evaluate how individual differences related to cognitive reserve and genetic risk modify the association between early brain changes and future cognitive decline. The overall hope is that this research will help generate a single, quantitative, MRI-based, risk score that can be used—in combination with pertinent health information—for identifying on an individual level asymptomatic persons at heightened risk for AD. Such persons may then benefit from more extensive AD biomarker testing, closer monitoring, and treatment with disease-modifying drugs when such drugs become available.
Janey Peterson, EdD, MS, RN
Assistant Professor
Weill Cornell Medical College
NSPIRE: Intervention to Support Participation in Regular Exercise in the Elderly
Older adults with multiple chronic diseases are at high risk for both disability and adverse clinical events, outcomes that can be improved with physical activity. However, there have been no trials to establish physical activity recommendations or clinical guidelines for this vulnerable population. The overall objective of this project is to tailor an intervention focused on induction of Positive Affect—a feeling of happiness and well-being— to the clinical and psychosocial needs of older adults with multiple chronic diseases in order to achieve long-term maintenance of physical activity in this high risk group.
Vivek Prabhakaran, MD, PhD
Assistant Professor
University of Wisconsin-Madison
Stroke Plasticity
Stroke is the fourth leading cause of death in the United States as well as the leading cause of long-term disability. Each year about 800,000 people suffer a new or recurrent stroke in the United States. 85% of these patients survive and require rehabilitation, making it the leading cause of long-term disability in the U.S. Although there are already several rehabilitation techniques aimed at stroke recovery few guidelines exist for these interventions. Dr. Prabhakaran’s research project is designed to characterize brain plasticity changes using neuroimaging measures and: 1) identify prognostic predictors in terms of neuroimaging and clinical measures so specific rehabilitation treatment plans can be tailored for a particular patient based on these predictors 2) identify a time window using neuroimaging measures which best predicts stroke recovery where stroke interventions may be maximally effective and 3) characterize the brain networks involved in stroke recovery so interventions can facilitate adaptive networks and suppress maladaptive networks which may lead to faster and more optimal rehabilitation.
The results of this research could establish the groundwork for utilizing neuroimaging as an objective tool for stroke rehabilitation and could potentially help in the designing of effective patient specific rehabilitation plans.
Chiao-Lin Chen, Ph.D.
Harvard Medical School
Dissecting the relationship between mitochondrial changes and aging
Despite the fact that decreased and/or dysfunctional mitochondrial activity is known to be characteristic of the normal aging process and of neurodegenerative diseases, the impact of aging on mitochondria is not clear. Part of the reason for this lack of clarity is that many mitochondrial components have not been identified, while many that have been identified have not yet been functionally characterized. To identify the components and age-related dynamics of the entire set of proteins localized in mitochondria, Dr. Chen will apply a novel protein-labeling technique that allows the isolation and identification of endogenous proteins from different compartments of the organelle. Since it is known that a class of Forkhead box proteins (FOXO) plays a role in regulating aging in a variety of species, Dr. Chen will examine the role of FOXO in the expression of mitochondrial proteins during aging. Her study will provide a comprehensive functional characterization of mitochondrial proteins and a data set for detailed analysis of the ways in which mitochondrial components integrate into physiological pathways that affect the aging process.
Alexis Cogswell, Ph.D.
Northwestern University
The role of the stem cell niche in regeneration and longevity in planarians
Aging and age-related diseases have long been studied using model organisms, including yeast, fruit flies, worms, and mice. Some studies suggest that aging of the model organism correlates with decreased stem cell numbers or altered stem cell function. However, it is not known whether the signals to maintain healthy stem cells come from within the cell or from the microenvironment surrounding the cell, also referred to as the stem cell niche. The flatworm Schmidtea mediterranea is a model organism that has been used to study stem cell biology for many years. These flatworms have the ability to regenerate all of their tissues and organs from very small fragments following amputation. This remarkable regenerative capacity is due to a population of adult stem cells which make up 20-30% of the total cells in the worm. These stem cells have been found in clusters surrounding the intestine, an area that may represent a stem cell niche for the flatworm. Dr. Cogswell will use the flatworm model to determine how the environment around the intestine maintains stem cell function and longevity.
Christin Glorioso, Ph.D.
Massachusetts Institute of Technology
Harnessing SNPs to investigate Sirtuin regulation of human brain aging
Anyone familiar with the excitement caused by claims that red wine just might contribute to a longer, healthier life has at least a passing acquaintance with the Sirtuin family of genes. The resveratrol found in the skins of red grapes is a Sirtuin gene activator. Increasing the amount or activity of various Sirtuins in mice has been shown to extend lifespan, slow normal brain aging, and/or delay various neurodegenerative diseases, including Alzheimer’s, Parkinson’s and Huntington’s. Before the potential benefits of using Sirtuin-stimulating drugs in humans can be explored, more research is needed into the function of the Sirtuin genes in human brain aging. Dr. Glorioso’s strategy is to identify variations in these genes that are associated with altered rates of normal human brain aging using a transcriptome-based biosignature. The team will then use cellular models to identify the mechanisms underlying these associations. Dr. Glorioso’s studies should help clarify the roles and mechanisms of Sirtuin regulation in human brain aging and inform potential therapeutic strategies.
Deborah Toiber, Ph.D.
Massachusetts General Hospital
The histone deacetylase SIRT6 modulates genomic stability, neurodegeneration and aging
Even though multiple studies have linked aging to chronic accumulation of DNA damage, the molecular mechanisms behind this phenomenon have not been determined. A class of proteins called sirtuin (SIR) is known to influence a wide range of cellular processes. One sirtuin, SIRT6, is an enzyme involved in DNA repair and metabolism. SIRT6-deficient mice die of an inadequate supply of glucose to their brains at 4 weeks of age. These mice show signs of premature aging and instability in the processing of genetic information. Conversely, mice with high SIRT6 activity live longer than normal lives. SIRT6 is the first mammalian sirtuin to be linked to increased life expectancy. Dr. Toiber will investigate whether low levels of SIRT6 in the brain can lead to premature neurodegeneration. She will document the effects of SIRT6 impairment at behavioral and molecular levels. Her goal is to learn what modulates how brain cells respond to DNA damage and what causes the damage response to become less efficient in old age.
Meltem Isik, Ph.D.
Joslin Diabetes Center
Investigation of TORC1- inhibition dependent SKN-1/Nrf activity and its effect on longevity
Just as people respond to their environments after taking in signals through different senses, cells respond to their environments via specific biochemical signaling pathways. Target of rapamycin, or TOR, is an enzyme that modifies other proteins. The signaling pathways that include TOR play roles in regulating cell growth, reproduction, movement, and ultimately survival. Environmental cues, such as temperature and availability of food, activate or repress TOR pathways and result in changes in cellular activities. Rapamycin, a drug that suppresses the body’s immune system response, inhibits TOR activity. The drug is used primarily to keep the body from rejecting transplanted organs. However, it is also the only drug that has been shown to slow normal cell aging processes in mammals. Unfortunately, rapamycin has some nasty side effects, such as causing diabetic symptoms and, not surprisingly, unhealthy suppression of the immune system. Dr. Isik’s research will examine how rapamycin affects cellular aging process. Her goal is to identify ways to reinforce the beneficial outcomes of inhibiting TOR by avoiding the immune system problems, insulin sensitivity and other undesirable outcomes of inhibiting critical TOR functions.
Brice Keyes, Ph.D.
The Rockefeller University
Molecular mechanisms of aging in hair follicle stem cells
Stem cells residing within the skin are responsible for maintaining and repairing epidermal tissue in response to normal wear and injury. But as we age, our skin decreases in both dermal and epidermal thickness, the epidermis loses its ability to self-repair, the dermis loses elasticity and wrinkles, we lose our hair and we are increasingly susceptibility to infection and cancer. The relationship between age-related declines in skin function and epidermal stem cell biology has not been documented. Dr. Keyes’ study will strive for a greater understanding of how stem cells change with age and how these changes influence tissue function. His work will provide insights to how hair follicle stem cells change molecularly over time and the importance of these changes to age-related characteristics in skin physiology. He will evaluate hair follicle stem cells purified from young and old animals for functional differences and determine the relevance of these differences to age-related changes in skin function.
Ranveer Singh Jayani, Ph.D.
University of California, San Diego
Roles of variants of the 9p21 gene locus, enhancers and non-coding RNAs in human cellular aging
Over the past decade, the most important goal in the field of aging research has been to understand the molecular events underlying the natural changes that take place within cells as we age. Old, compromised cells are a source of many toxic and inflammatory factors that promote symptoms of aging. Researchers envision molecular approaches to intercede in the cellular aging process in order to delay or treat age-related dysfunction and disease. The focus of Dr. Jayani’s investigation is the “enhancer codes” regulating specific genes on chromosomes that are closely associated with aging-related diseases, such as coronary artery disease and type-2 diabetes. The genetic location he has identified is known to be a key regulator of pathways involved in cellular aging and tumor formation because it is home to age-associated genes. He will study the influence on regulation of these genes by enhancer Ribonucleic acids (RNAs) and document the molecular mechanisms underlying regulation of the enhancers within the targeted genomic region. His work will shed light on a new model of regulation of gene expression and deepen our understanding of biological aging.
Caroline Kumsta, Ph.D.
Sanford-Burnham Medical Research Institute
Linking autophagy and stress response pathways in C. elegans longevity models
As the cells of the body go about their work, garbage is created in the form of unnecessary or dysfunctional cellular components. Clearing out this waste material is an important part of maintaining healthy cells. One of the characteristics of aging is a weakening of our cells’ ability to clean up after themselves, which can lead to accumulation of harmful cellular debris and to loss of proper cellular function. Our cells use several waste management processes, including stress response pathways and the recycling mechanism called autophagy, which comes from the Greek self (auto) to eat (phagyein). Effective stress response and autophagy are involved in increasing the lifespan of various organisms including the round worm C. elegans. Using this model organism, Dr. Kumsta will research whether there are biochemical regulators common to stress response pathways and autophagy. Identifying these regulators will help scientists understand the interplay between the two processes and could form the basis for developing strategies to keep cells healthy and youthful, thereby delaying the onset of cellular decline and age-related diseases.
Elena Mancini, Ph.D.
Stanford University
Unveiling aging and rejuvenation mechanisms through cellular reprogramming
Rejuvenation, the reversal of the aging process, has long been a quest of mankind, having spawned myths, legends and scientific study. Rejuvenation seeks to repair the damage associated with aging or replace damaged components with new ones. Intriguingly, scientists have learned that adult human cells can be “reprogrammed” into embryonic stem-like cells called induced pluripotent stem cells, or iPSCs. iPSCs to be used to combat diseases common to the elderly, such as neurodegenerative diseases, stroke, and heart failure, will have to be derived from older individuals. Recent evidence suggests that iPSCs can indeed be generated from old cells and that reprogramming rejuvenates some age-related aspects of the cells. However, the systematic impact of aging on reprogramming is still not fully explored. The goal of Dr. Mancini’s research is to examine the impact of age and longevity genes on iPSC generation and quality, and to study whether reprogramming can rejuvenate aged cells. The project should provide invaluable information on the fundamental mechanisms of aging and rejuvenation, and lead to clinical applications of iPSCs in regenerative medicine.
Antoine Emile Roux, Ph.D.
University of California, San Francisco
A new experimental system of rejuvenation to study aging
Dr. Roux has set out to find biomarkers for use as a basis for determining why we age. Using C. elegans as his model, he observed the behaviors of biomarkers typically associated with dysfunction and disease related to aging, such as aggregation of proteins, the loss of mitochondrial network integrity, oxidative stress, among others. The appearance of all of these markers increased with age and was delayed in long-lived worms. Dr. Roux then discovered a new rejuvenation-like mechanism. When newly-hatched worm larvae were deprived of food, instead of dying they slowed down their metabolism, entered a state of developmental arrest and survived for weeks. During this period the aging markers appeared, just like during normal adult aging. But after the arrested larvae were fed, they initiated development and their cells rejuvenated, erasing the markers of aging. This was the first description of a rejuvenation mechanism of somatic tissues, independent of reproductive tissue. Dr. Roux’s new project will screen for the genes involved in this rejuvenation process with the hope of eventually finding universal aging mechanism and biomarkers through the perspective live-animal microscopy.
Qian Qi, PhD.
Stanford University
Mechanisms of memory T cell inflation in immune aging
The ability of the immune system to fend off infectious organisms or to control chronic infections declines with age. Part of the problem, Dr. Qi has observed, seems to be immune system resource mismanagement. The decline of the aging immune system is accelerated by certain chronic infections that are otherwise not very harmful. For reasons unknown, the immune system over-commits resources to control these less dangerous infections, thereby compromising other important functions in the elderly. One infection in particular, chronic cytomegalovirus (CMV), has been implicated in the acceleration of the aging process by creating an imbalance among the cells sent to fight and isolate the infection, thereby further disrupting the deteriorating immune system. Consequences for the elderly include reactivation of zoster infections and increased morbidity and mortality from influenza. Dr. Qi’s new research project seeks to understand which control mechanisms fail, leading to this harmful misallocation of resources. Identifying signaling proteins that are important for regulating the immune system response but which fail when fighting CMV infection will provide important insights to the mechanisms of immune aging.
Collin Y. Ewald Ph.D.
Harvard University
The impact on aging of preferential translation of ATF-5
A cell can be viewed as a factory that assembles its own parts (proteins) to maintain itself. With age, the assembly lines wear out and more and more malfunctioning parts (misfolded proteins) are produced. It stands to reason that reducing the amount of malfunctioning protein in the system should reduce the symptoms of aging and promote longevity. Recent work with yeast suggests that longevity is characterized by an increase in a small selection of proteins that clean up cellular garbage while general protein production is put on hold. Dr. Ewald and colleagues have identified such a janitor-like protein, ATF-5, that prolongs lifespan in the nematode worm C. elegans. ATF-5 is specifically activated when global protein production is reduced. Dr. Ewald will investigate both how ATF-5 is activated and the mechanisms by which it increases lifespan. He will identify regulators of ATF-5 that mimic reduced protein production conditions and will identify which proteins are instructed by ATF-5 to promote longevity. This work could identify therapeutic targets for ensuring longer, quality lives for people by postponing age-dependent and chronic diseases.
Ying Ann Chiao, Ph.D.
University of Washington
Reversal of cardiac aging by sub-acute treatment with rapamycin
Preliminary research using rapamycin, a drug used to prevent organ rejection during transplants, has shown that the drug can reverse symptoms of an aging heart, such as unhealthy enlargement and a decline in its ability to relax and fill with blood. However, how rapamycin works its rejuvenative magic is not understood. Dr. Chiao’s research will characterize the protective effects of rapamycin on cardiac aging and determine the mechanisms that confer these benefits. She and her team will compare cardiac function, and physiology of young and old mice fed with rapamycin to confirm that treatment can reverse cardiac aging in old mice. They will document how the drug reverses age-related changes in mitochondrial protein expression, turnover and function and determine if the rapamycin benefit is mediated by a metabolic shift in old hearts. Overall, this study will evaluate the potential of rapamycin as an intervention to prevent and possibly even reverse cardiac aging.
Karl A. Rodriguez, Ph.D.
The University of Texas Health Center San Antonio
Chaperone-mediated protein degradation contributes to longevity and health span in the long-lived naked mole rat
Looking at a naked mole-rat, it can be hard to imagine that this bald creature has anything to teach humans about aging. But it turns out they enjoy extraordinary longevity and maintain good health for the great majority of their long lives. The naked mole rat lives 32 years, 8 times longer than a similarly sized mouse. Among the necessities of a long life is the ability of the cell to maintain healthy proteins for proper function. It is also critical for both cell and organism survival that irreparably damaged proteins are removed. Molecular chaperones assist in the repair of these damaged and misfolded proteins. Dr. Rodriguez will examine how chaperones sustain, maintain, and protect the process of protein turnover in naked mole-rats compared to the short-lived mouse to find one of the mechanisms behind incredible health and longevity of this much longer-lived species. His study focuses on two different pathways of chaperone-assisted, protein degradation in order to understand their role in regulating protein homeostasis and its role in healthy aging.
Phillip Jaeger, Ph.D.
University of California, San Diego
A genome-wide analysis telomere maintenance and cellular senescence
The nature of the DNA-replication process causes chromosomes to shorten during each cell cycle. Genes at the ends of chromosomes would become truncated and useless over time if not for the protection provided by specialized structures called telomeres. Telomeres buffer the genes at the ends of chromosomes from damage and can be restored to full-length after each cell division by a protein complex called telomerase. Theoretically, telomeres allow cells to undergo infinite divisions without degradation. Unfortunately, telomerase activity is restricted to stem cells, so cells that make up specialized tissues such as the heart don’t have the potential to replicate indefinitely; therefore, the tissue progressively decays as we get older. Dr. Jaeger will use a series of experiments to build a comprehensive genetic network model of genes that influence telomerase activity in yeast and mammals. This knowledge will then be used to predict genes that might be involved in telomerase regulation in higher organisms, including humans, and to identify genes that could be manipulated to safely regulate telomerase function and delay cellular aging while minimizing cancer risk.
Lifen Wang, Ph.D.
Buck Institute for Research on Aging
Age-related stem cell deregulation by ER stress in intestinal stem cells in Drosophilia
Adult stem cells have the ability to replenish dying cells in our tissues and organs, thereby counteracting much of the wear and tear our bodies experience every day. However, stem cell function declines with age due to environmental factors or to internal stresses such as toxins, inflammation, misfolded proteins or oxidative stress. Dr. Wang will explore the role of an important stress response mechanism in age-associated stem cell deregulation in the intestines of small flies. Intestinal stem cells (ISCs) reproduce at an abnormally high rate in aging flies, resulting in excessive tissue creation and negatively impacting intestinal function. Dr. Wang’s preliminary data suggest that this is caused primarily by a specific stress in ISCs. She will explore the signaling mechanisms that control stem cell proliferation associated with this stress response and test whether improving protein activity in these cells is sufficient to increase tissue health and lifespan. Her findings will allow deeper insight into the causes and consequences of age-related stem cell deregulation and could lead to strategies to prevent stress-induced deregulation of stem cell activity.
Mara McAdams DeMarco, Ph.D.
Instructor
Johns Hopkins Medical Institutions
The burden, risk factors, and consequences of gout in older adults
Gout is the most common form of inflammatory arthritis and disproportionately affects adults over the age of 65. Although, the incidence of gout increases with age, no study has thoroughly investigated the disease specifically in older adults. Dr. McAdams DeMarco’s epidemiology study will address three important knowledge gaps among older adults: 1) the incidence and prevalence of gout in subgroups, such as women, African Americans, and patients with a history of osteoarthritis, 2) the ability of traditional and novel risk factors to predict the development of gout as we age, and 3) the impact of gout on physical function. The team will use the valuable infrastructure of a population-based cohort study Atherosclerosis Risk in Communities (ARIC), which has over 15,000 diverse participants who have been tracked for 25 years. The findings from the team’s research will directly benefit the nearly five million older patients who suffer from gout and their healthcare providers by better characterizing this disease in an understudied population.
