Ellison Medical Foundation/ AFAR Postdoctoral Fellows
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.