The Paul F. Glenn Center for Biology of Aging Research
Professor, Molecular and Cell Biology Laboratory
Donald and Darlene Shiley Chair for Research on Aging
(858) 453-4100 x1867
My laboratory is interested in telomere dynamics during the cell cycle, aging, senescence and cancer formation. We are focusing on telomere maintenance pathways and their regulation during cellular transformation, on telomere structure, telomere replication, the interaction between the checkpoint machinery with telomeres, the impact telomeres have on nuclear structure, telomere localization and telomere-driven epigenetic changes during cellular and organismal aging and transformation. The laboratory’s recent discovery that mitotic inhibition leads to telomere dysfunction promotes the hypothesis that side effects associated with treatment of mitotic inhibitors, such as accelerated aging phenotypes, could be due to telomere deprotection. Furthermore, we are exploring the effects of mitotic inhibition on telomere crisis, genome instability and cancer formation.
The Paul F. Glenn Center for Biology of Aging Research
Professor, Molecular and Cell Biology Laboratory
Ralph S. and Becky O'Connor Chair
(858) 453-4100 x1913
During human life span, lungs, skin, liver and other organs are constantly replenished by newly divided cells. However, most human cells cannot divide indefinitely. Instead, cells have a "clock" that counts down the number of times a cell can divide—and once this countdown is complete, the ability to withstand the degenerative aspects of aging declines.
Vicki Lundblad discovered that the molecular basis for this clock resides at the very ends of our chromosomes. These chromosome ends—called telomeres—get nibbled away with each cell division until they become so short that cells are prevented from dividing further. Although Lundblad first uncovered this process in a simple single-celled organism, subsequent studies have shown that whether this telomere clock counts down faster or slower in human cells is a contributing factor to age-dependent diseases such as bone marrow failure, pulmonary fibrosis and late-onset diabetes.
However, this clock can be re-set by a telomere-dedicated machine called telomerase which re-elongates telomeres, thereby rescuing them from oblivion. Lundblad's group pioneered the discovery of the components of telomerase, once again using a single-celled organism (the yeast S. cerevisiae –the same yeast used to make wine and bread!). Because the process of cell division is basically the same in baker's yeast and human cells, her laboratory's findings provided the tools for uncovering the components of human telomerase.
With telomerase components in hand, this has allowed experiments to determine why the telomere clock might count down faster in some cells. Lundblad postulated that these variations are likely due to be how telomerase finds its way to chromosome ends in order to re-set telomere length. In support of this, her laboratory has shown that the surface of telomerase has multiple docking sites that ensure its efficient delivery to chromosome ends. Her group also discovered that the telomerase complex is disassembled during every cell division, which they speculate provides a mechanism for keeping telomerase at exceptionally low levels inside cells. These insights provide clues into how telomerase might be manipulated to promote healthy aging.
Molecular Neurobiology Laboratory
Our team is interested in understanding how neural circuits decode environmental changes to drive behavior. We use the nematode, C. elegans and the vertebrate D. rerio as models to study brain functions.
The C. elegans nervous system consists of just 302 neurons that are connected by identified chemical and electrical synapses. Despite its simplicity, this animal displays a number of sophisticated behaviors providing us with an ideal model to study neural circuit properties.
What is a neural circuit? A neural circuit is a defined as a set of interconnected neurons whose activation identifies a pathway for information to flow and often results in a behavioral output. We have recently found that in the chemosensory system, the configuration of the neural circuit is dynamic and changes based on sensory context. We found that sensory neurons come in two flavors: primary sensory neurons that directly detect stimuli and secondary neurons that respond to signals from the primary neurons. This suggests that sensory information is encoded by the combined activity of both primary and secondary neurons. We have also discovered this primary to secondary neuron signaling is degraded during aging and that this loss might underlie the aging-associated decline in olfactory function. We are currently dissecting the mechanisms that regulate aging process at the level of genes, neural circuits, tissues and whole animals.
Laboratory of Genetics
Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease
Human aging is the main risk factor for several diseases including neurodegenerative disorders such as Alzheimer’s or Parkinson’s disease. To better understand the pathogenesis of these diseases, the in vitro generation of human neurons for disease modeling is an attractive approach. However, preservation of human aging as a major pathogenic risk factor would seem unlikely given that cells must transit the embryo-like induced pluripotent stem cell (iPSC) state. We generated iPSCs from a broad range of aged donors and found that, in contrast to primary skin fibroblasts, iPSCs rejuvenated their transcriptomic memory of donor age. Alternatively, direct conversion into functional induced Neurons (iN) preserved transcriptomic signatures of age. Importantly, iNs from aged donors showed a highly age-dependent decrease in several very interesting and relevant genes including genes encoding proteins important for nuclear transport and importantly these genes and their corresponding protein are also down regulated in old fibroblasts as well as in the aging human prefrontal cortex. Using a reporter system for nucleo-cytoplasmic compartmentalization (NCC), we detected an age-dependent loss of NCC in old fibroblasts and neurons. In addition, we demonstrate that a reduction of key protein was sufficient to impair NCC in young cells. In contrast, iPSC rejuvenation completely restored NCC in old cells. Our data demonstrate that, unlike iPSCs, directly converted iNs retain important molecular and functional signatures of the age of their donors, thus allowing for a new model of aging in vitro. The data also identify impaired protein compartmentalization between nucleus and cytoplasm as an important factor involved in human aging.
Molecular and Cell Biology Laboratory
Jesse and Caryl Philips Foundation Chair
Age is the major risk factor for the development of cardiovascular, pulmonary, neurodegenerative and several other human diseases. The fundamental defining feature of aging is an overall decline in the functional capacity of various organs, which in turn results from deterioration of homeostasis within their constituent cells. Our lab uses emerging technology to study how organs in the adult body—primarily focusing on the heart and the brain—are maintained. We are particularly interested in identifying the mechanisms underlying their functional decline during aging. These studies are relevant from a public health standpoint as they hold the promise of revealing new principles of tissue homeostasis and age-related loss of function during “normal” and pathological aging.
We have recently discovered that nuclear pore complexes (NPCs) are extremely long-lived in post-mitotic cells and deteriorate over time, causing a loss of cell compartmentalization in old neurons. Our results suggest that nuclear pore deterioration might be a general aging mechanism leading to age-related defects in nuclear function, such as the loss of youthful gene expression programs. Age-dependent deterioration of NPC function and the associated failure of the nuclear permeability barrier are characterized by the leaking of cytoplasmic proteins into the nucleoplasm. We detected large filaments inside the 'leaky' nuclei of old mouse and rat neurons, which stained with the cytoplasmic protein tubulin. Strikingly, tubulin-positive intranuclear structures have been linked to various neurological disorders in humans. Our studies provide a new perspective on the cellular organization of neurons and suggest that long-lived NPCs might contribute to their functional decline during aging.
Our recent results also suggest that, in addition to NPCs, additional proteins exist that are as old as the cell and organism they reside in. A metabolic, pulse-chase labeling study performed in rats suggests that long-lived proteins (LLPs) might be much more prevalent than previously thought and might be critical for the function and aging of neurons. In the future, we will study the biochemical properties of LLPs and explore the idea that previously identified protein repair mechanisms might enable them to persist for years. In addition, we will study why protein longevity might have evolved and test if the functional decline of LLPs might explain age-related changes observed in neurons.
Professor, Gene Expression Laboratory
Roger Guillemin Chair
In modern societies, aging remains the leading risk factor for neurodegenerative disorders, cardiovascular diseases and cancer. Aging can be defined as the progressive decline in the ability of a cell or an organism to resist stress, damage and diseases. Hutchinson–Gilford progeria syndrome (HGPS) is a rare premature aging syndrome caused by mutations in the LMNA gene, resulting in the accumulation of a truncated form of lamin A known as progerin that leads to abnormal nuclear morphology. Over the last decades, accumulated evidence has demonstrated that mitochondrial dysfunction and oxidative stress are among the phenotypes associated with the aging process. During life, a progressive decline in mitochondrial function leading to oxidative damage to macromolecules constitutes the central dogma of the “Free Radical” theory of aging. However, despite being classified as a premature aging syndrome, the role of mitochondrial dysfunction in progeria has not been investigated. We have generated induced pluripotent stem cells (iPSCs) from fibroblast obtained from progeria patients. Differentiation to vascular smooth muscle cells and mesenchymal stem cells (MSCs) recapitulates the premature aging phenotypes. Interestingly, progeria MSCs present a distinct transcriptome signature with significant alterations in central carbon metabolism, including glycolysis and TCA cycle, in addition to reducing mitochondrial respiration and increasing oxidative stress. GC/MS and isotope tracing experiments reveal significant deficiency in glutamine metabolism in progeria MSCs. We propose that metabolic dysfunction could be one of the major drivers of premature aging in HGPS patients and hypothesize that genetic and pharmacological manipulations aiming to restore metabolic function will alleviate the devastating effects of this and other premature aging syndromes as well as normal aging.
Plant Biology Laboratory
One major aspect controlling gene expression in eukaryotic organisms involves the addition of specific chemical groups, termed epigenetic modifications, to DNA and histones—two major components of chromatin. These modifications influence the expression of the underlying genes and play critical roles in diverse biological processes including imprinting, development and gene silencing. My laboratory studies the mechanisms through which these patterns of chromatin modifications are established and interpreted. In particular, we are interested in repressive modifications, like DNA methylation, that contribute to global genome stability, through the silencing of transposable elements, and to cellular identity, through the silencing of genes in a developmentally programmed manner. Attesting to the importance of proper DNA methylation patterns, aberrant DNA methylation is associated with both acute and chronic effects on development and human health. This includes numerous age-related diseases such as heart disease, cancer and a variety of neurological and autoimmune disorders. To understand how changes in DNA methylation arise and how they contribute to the progression of age-related diseases, a detailed understanding of the proteins and pathways controlling DNA methylation is required. This information will not only be key in understanding how epigenetic processes can contribute to the progression of diseases, but also in determining how specific manipulations of DNA methylation pathways can be employed for gene therapy.
Over the past two years, my laboratory has focused on identifying and characterizing chromatin effectors, including chromatin remodeling complexes and histone binding proteins, that link epigenetic modifications with the machinery required to orchestrate critical processes associated with genome stability using the plant model Arabidopsis thaliana. Using a combination of genetic, biochemical and genomics approaches, we aim to determine the epigenetic marks recognized by these chromatin factors, identify their interacting partners, and investigate their effects on gene expression and higher order chromatin structure, providing a holistic view of the events occurring downstream of epigenetic modifications.
Arabidopsis is an ideal model organism to study epigenetic processes as it is genetically malleable, highly amenable to genomic analyses and tolerant of dramatic changes in its epigenetic landscape, setting it apart from other model organisms. In addition, many of the proteins and pathways involved in epigenetic processes are conserved between plants and mammals. Thus, our work takes advantage of the speed and genetic malleability of a model system while maintaining a high level of relevance to human health and disease that may ultimately aid in the development of tools capable of correcting epigenetic-based defects.
Clayton Foundation Laboratories for Peptide Biology
J.W. Kieckhefer Foundation Fund Chair
When a person’s blood sugar level is high even when the person hasn’t recently eaten—known as an “elevated fasting glucose level”—it provides a first clue that he or she is at risk of developing type 2 diabetes.
Finding ways to lower blood glucose offers great promise for diabetes treatment because doing so reduces the risk of the many diabetes complications that substantially affect the quality of life. The need for new drugs is accelerating as almost 26 million Americans have type 2 diabetes, and an estimated 79 million people are at risk of developing the condition.
During the day, when we feed, we use high-octane glucose from the food we take in to get around. And at night, when we fast, our body shifts to burning the fat from adipose stores, which provide a lower-power but longer-lasting source of energy.
Although most organs in the body can use glucose or fat as a source of energy, the brain requires glucose during both night and day. The liver assumes this task during fasting, when it becomes a glucose-producing organ. Obese individuals with insulin resistance produce too much glucose, leading to elevated glucose levels in the bloodstream that contribute to the development of type 2 diabetes. Our lab identified the function of a genetic switch, called CRTC2, which controls the production of glucose by the liver during fasting and in diabetes. We found that the CRTC2 switch is turned on in liver cells during fasting in response to a hormone called glucagon. Glucagon flips the CRTC2 switch on in liver cells by causing a chemical change in CRTC2 known as de-phosphorylation. Our group showed that inactivating the CRTC2 switch blocked the hormone’s ability to stimulate glucose production by the liver during fasting.
In recent studies, the lab has determined that the CRTC2 switch controls glucose production through an enzyme that associates with the switch. Inactivating this enzyme with a small molecule inhibitor was sufficient to lower blood glucose levels in obese, insulin-resistant mice. These findings may offer new targets for drug development and provide effective therapies for the treatment of type 2 diabetic individuals.
Regulatory Biology Laboratory
Rita and Richard Atkinson Chair
Our team explores how our biological clocks control our metabolism and physiology as a means for coming up with new strategies to treat or prevent chronic diseases. Our lab discovered that a light receptor, called melanopsin, senses blue light in our environment and tells our brain when to sleep and when to stay alert. The discovery has inspired architects and designers to redesign lighting at workplaces, homes and hospitals to improve the quality of life. The team is also actively pursuing a novel idea for finding drugs that can mimic light or dark so that diseases like depression and sleep disorders can be effectively treated.
Our work on clocks outside the brain revealed that eating times synchronize clocks in other organs, including the liver, muscles and fat tissues. These clocks, in turn, orchestrate when and for how long our body breaks down sugar, fat and cholesterol.
We may have found another option for preventing obesity by preserving natural feeding rhythms without altering dietary intake. We discovered that mice who ate fatty food frequently throughout the day gained weight and developed high cholesterol, high blood glucose, liver damage and diminished motor control, while the mice restricted to eating for only eight hours per day weighed 28 percent less and showed no adverse health effects, despite consuming the same amount of calories from the same fatty food. When given an exercise test, the time-restricted mice also outperformed the ad-lib eaters and control animals fed a normal diet. The findings suggest that the control of energy metabolism is a finely tuned process that involves an intricate network of signaling and genetic pathways, including nutrient-sensing mechanisms and the circadian system. Time restricted feeding acts on these interwoven networks and moves their state toward that of a normal feeding rhythm.
Molecular and Cell Biology Laboratory
Audrey Geisel Chair in Biomedical Science
The overall goal of the research in my laboratory is to understand the role of mitochondria and associated stress-signaling pathways in human disease, immunity and aging. Below is a summary of our activities with regard to aging and age-related disease pathology.
Mitochondrial ROS signaling in aging and disease. Mitochondria have long been implicated in aging, being central to the long-held “mitochondrial” and “free radical” theories that suggest functional declines in energy metabolism and increased reactive oxygen species (ROS)-mediated damage are causative. However, recent advances, including those I will summarize here from my lab, have begun to redefine how mitochondria fit into the major longevity pathways and influence aging. One of the major known longevity pathways involves flux through the mechanistic target of rapamycin (mTOR) kinase. This nutrient-sensing pathway was discovered in yeast and we used this genetic model system to probe the mechanism of longevity regulation mediated by reduced mTORC1 signaling. We found that reduced mTORC1 signaling extends yeast chronological lifespan by flipping a switch in metabolism toward mitochondrial respiration and increased ROS production. These mitochondrial ROS cause, via signaling (not damage), adaptive changes in nuclear gene expression that increase stress resistance and longevity. Specifically, mitochondrial ROS signal through the yeast homolog of the DNA-damage-sensing kinase ATM (Tel1p) to silence subtelomeric chromatin by inactivating a histone demethylase called Rph1p. Our yeast studies, in combination with those by others in C. elegans, has led to a paradigm shift in the thinking about mitochondrial in aging, where mitochondrial stress signals activate adaptive, pro-longevity responses (sometimes referred to as “mitohormesis”). Ongoing efforts in my lab are directed toward translating these exciting studies into mammals to understanding how mitochondrial stress impacts aging and age-related diseases. We are also actively pursuing how mitochondrial ROS activate ATM and contribute to Ataxia-telangiectasia, a neurodegenerative and progeroid disease.
Mitochondria in innate immune signaling, age-related inflammation and cancer. We discovered that mitochondrial DNA (mtDNA) can be released into the cytoplasm of cells, where it activates pro-inflammatory innate immune signaling (i.e. mtDNA-cGAS-STING pathway). Others have shown that mtDNA can activate other immune sensors (e.g. TLR9 and inflammasomes) to cause inflammation. Since mtDNA becomes damaged, mutated and unstable with age, we hypothesize that it activates these immune pathways and contributes significantly to the chronic inflammation experienced with aging. We are actively pursuing multiple lines of investigation aimed at understand how mtDNA-driven inflammatory pathways contribute to aging, neurodegeneration and cancer.
Molecular and Cell Biology Laboratory
William R. Brody Chair
The central goal of our research is to elucidate mechanisms by which cells connect nutrient availability to cell growth and metabolism. Our work is focused on a highly conserved signal transduction pathway controlled by the AMP-activated protein kinase (AMPK) that, when deregulated, leads to cancer and metabolic disease. Activation of AMPK by the tumor-suppressor LKB1 under conditions of energy stress serves as a central switch that reprograms glucose and lipid metabolism and halts cell growth. LKB1, which encodes a serine/threonine kinase that is the cause of the inherited cancer disease Peutz-Jeghers syndrome, is also one of the most commonly mutated genes in lung cancer.
Current efforts in our laboratory are aimed at further identifying the key components of the LKB1-AMPK signaling pathway that suppress tumorigenesis and metabolic disease, as well as decoding the circuits linking fundamental cell biological processes to physiology. We employ a variety of biochemical, cell-biological, and genetic mouse models to dissect these biological processes. The discovery of this ancient energy-sensing pathway has already led to fundamental insights into the mechanisms through which all eukaryotic organisms couple their growth to nutrient conditions and metabolism. A deeper understanding of the key components of this pathway connecting metabolism and cell growth will instruct us how to best exploit these endogenous mechanisms to combat specific forms of cancer and type 2 diabetes.
NOMIS Center for Immunobiology and Microbial Pathogenesis
The immune system undergoes profound changes with the increase of age. In old adults, a significant decline occurs in the immune system’s ability to respond to vaccination and to protect the host against infection. Regulatory T cell (Treg) is a subset of T lymphocytes that suppress excessive immune response and prevent autoimmune diseases. The number of regulatory T cells increases substantially during the aging process compared to other T cell sub-populations in humans and mice. The expansion of Tregs in old individual can amplify their immunosuppressive function, and lead to compromised immune response against infection and tumor. Currently, the signals that drive Treg expansion during aging are poorly understood. It is also not clear if Tregs from aged individual retain the same immune suppression capacity as Tregs from the young. We are currently studying the dynamics of the Treg population during aging and characterizing the molecular signatures of aged Treg cells. Through our studies, we hope to develop strategies to manipulate Tregs to fine-tune the immune system in aged setting to fight against infections and cancer.