Ellison Scholars

Ellison Medical Foundation Scholars

Funding from the Ellison Medical Foundation has supported aging research by several Jackson Laboratory investigators.


Mammalian Somatic Mutations and Aging
Matthew Hibbs, Assistant Professor, The Jackson Laboratory
2011 New Scholar Award in Aging

The accumulation of somatic (non-heritable) DNA mutations over time is a hallmark and potential mechanism of aging. Current theory postulates that un-repaired, stochastic DNA damage results in random DNA mutations that accumulate over time within individual cells, and are passed on as these cells replicate. These mutations are thought to impair cellular function, or to induce cell death or senescence, leading to impaired organ function and aging. Alternately, rare mutations may lead to cellular transformation and cancer. These theories depend upon the extent of mutations accumulated in tissues with age, but we do not have an accurate measurement of the mammalian somatic mutation rate.

In the this study, we are using high-throughput sequencing and rigorous statistical methods to empirically measure the whole-genome somatic mutation rate in mice at multiple stages of adulthood and old age. We are assaying mutations in four diverse tissues, and in three genetically diverse mouse strains with varying lifespans. Our analyses of these data will determine the extent to which somatic mutations are associated with age, tissue, and genetic background. This multi-factorial study of somatic mutations will provide the most accurate measurement of the mammalian somatic mutation rate to date, will begin to define the parameters that control the accumulation of mutations with age, and will begin to empirically test common theories of cancer and aging.


Aging Research Using the Diversity Outbred Mice
Gary Churchill, Professor, The Jackson Laboratory
2010 Senior Scholar Award in Aging

Only a handful of interventions are known to extend lifespan in mammals. Among these, dietary restriction is the best established. In a recent study by Harrison and others, rapamycin was the first drug demonstrated to increase mammalian lifespan. However, all known interventions that affect aging are accompanied by detrimental side effects. Pharmaceutical interventions are most appealing but there is still insufficient knowledge of mammalian aging at the mechanistic and genetic level to identify effective drug targets.

We will develop a comprehensive strategy for the discovery and validation of targets in a mammalian system that closely mimics the genetic state of humans. Our approach will utilize genetic variation in mice to identify the genes and pathways that can potentially regulate lifespan with minimal detrimental effects. Mice are remarkably similar to human beings: 99% of mouse genes have human counterparts. Yet, mice age 25 times faster than humans, greatly facilitating aging experiments. Genes identified in mouse studies can be evaluated in human populations by studying whether there is an association between people with one form of the gene and an increase in lifespan. If a gene proves to be important in human aging, researchers can return to the mouse to test methods of clinical intervention.

We propose to use a powerful new genetic approach to study the mechanisms that regulate aging and healthy lifespan. The diversity outcross (DO) is a novel mouse population that mimics human genetic diversity. Traditional drug treatment studies use populations with no genetic variance and compare responses to an intervention. Our strategy represents a new approach to target discovery in gerontology by identifying genes that regulate differential response to interventions affecting the aging process. Specifically, this project will assay parameters of healthy life span and immune and metabolic aging in DO mice under control, diet restriction and rapamycin treatment conditions. We expect the DO mice to show variation at least as great as seen in the human population. We will determine the genetic regions that mediate the effects of treatment interventions. Our long-term objective is to identify targets for interventions that will increase healthy life span.

Testing genes that may affect lifespan
Beverly Paigen, Professor, The Jackson Laboratory
2009 Senior Scholar Award in Aging

The major goal of our program is to identify aging genes in the mouse and then to test those genes in humans. The testing in humans will be carried out in collaboration with Dr. Joanne Murabito of Boston University, who will test these genes in individuals who have lived to at least 90 years of age compared with a control group. For those genes that test positive in humans, we will return to the mouse and generate a model to better explore the function of the gene in aging. To find the genes in the mouse, we will focus on lifespan quantitative trait loci that have been found in the mouse and that also have a genome wide association peak for longevity from a human study; there are 9 such locations. This project should identify genes that affect longevity in mouse and human and provide some insight into the biological mechanisms that promote longevity.


The roles of the stress response in aging and age-related diseases in humans
Chengkai Dai, Assistant Professor, The Jackson Laboratory
2009 New Scholar Award in Aging

In humans, aging is associated with two major life-threatening diseases: neurodegeneration and cancer. A number of theories have been proposed to account for the aging process. The stress theory of aging emphasizes that stressful environments cause cellular damages, disruption of cellular functions, and eventual organismal aging. In strong support of this notion, stress resistance noticeably correlates with lifespan extension across species. The stress response, an evolutionarily conserved adaptive mechanism, coordinates an extensive array of cellular pathways to resist a wide variety of environmental stressors and critically enhance cellular survival. Recent studies indicate that the stress response is a key regulator of lifespan in worms and protects against neurodegenerative disorders. Nonetheless, whether the stress response influences the lifespan of higher organisms still remains elusive.

While the stress response enhances viability and antagonizes neurodegeneration, likely delaying aging, a recent study of ours clearly reveals its startling role in supporting cancer. Thus, we hypothesize that the stress response may impact mammalian longevity and may act as a divergent mechanism in age-related human diseases – balancing neurodegeneration and cancer susceptibility. Understanding how the stress response functions in the aging process and related diseases in mammals, which is still largely unknown, has the potential to establish the stress response as a pivotal longevity pathway that has been conserved during evolution and to ultimately translate into ground-breaking interventions for aging and age-related diseases in humans. The primary objectives of this proposal are to elucidate the specific effects of the stress response on mammalian aging and longevity and to unravel the intriguing, divergent role of the stress response in two major age-related diseases in humans – blocking neurodegeneration, but promoting cancer.


Testing the Hypothesis that Regulation of Female Reproductive Aging is Cell Autonomous
David Harrison, Professor, The Jackson Laboratory
2007 Senior Scholar Award in Aging

Precursor cells that continuously regenerate are vital for health. In order to cure or postpone age-related functional deterioration and disease, it is necessary to identify which precursor cells regulate the rates of aging in various biological systems. Dr. Harrison and his associates are testing the degree to which senescence of the female reproductive system is intrinsic to specific cell types in the ovary, uterus, and specific regions of the brain. The female reproductive system is used because loss of function occurs with age before most lesions develop, thus avoiding complications due to lesions, as well as facilitating progress of the research.Chimeric mice will be created that combine cells from two genotypes, one with normal and one with delayed reproductive aging. Genetic markers will distinguish the two genotypes. Since cell fates are determined in the early embryo, with few cells present, the proportions of cells of each type in each organ should vary greatly from one organ to the next and from one chimera to the next. The key tissues timing female reproductive senescence will be identified as those in which high proportions of cells from the genotype with delayed reproductive aging correlate with long reproductive lifespan in the corresponding chimera. In future studies, such key tissues will be treated with young functional precursor cells in order to delay aging.


Causal Factors in Mouse Models of Aging
Shirng-Wern (Sharon) Tsaih, Research Scientist, The Jackson Laboratory
2007 New Scholar Award in Aging

This project will develop novel methods for causal inference utilizing multiple age-related phenotypes collected on a panel of mouse inbred stains across a range of ages at the Jackson Laboratory Integrative Center for Genetic Regulation of Aging. This unique study of mammalian aging will accelerate the pace of aging research. Graphical models are a rapidly emerging area of statistical inference that enable us to gain insights into causal relationships among multiple variables. Establishing causal relationship is especially important in aging studies to help distinguish primary causes for secondary reactions to biological changes that occur with age. By combining graphical modeling techniques with traditional longitudinal analysis, we will be able to elucidate the dynamic relationship over time. We will apply these techniques to study relationships among metabolic, body composition and blood chemical traits to identify those factors most likely to have direct effects on aging and age-related pathology. In particular, we hope to identify measurable traits that can serve as reliable early indicators of longevity and age related pathologies. By including both gene expression and genetic variation data in the graphical modeling techniques, we will be able to place measurements in a pathway affecting lifespan and to state which measurements are correlated with lifespan but are not causal. Hence this study will provide a unique and powerful statistical approach to identify those causal factors that have direct effect on aging and lifespan.


New Genetic Strategies in the Study of Aging
Kenneth Paigen, Professor, The Jackson Laboratory
2006 Senior Scholar Award in Aging

We sense aging as something that happens to our bodies, but as scientists we know that the underlying causes lie in the subtle, and sometimes not so subtle, changes that go on in our cells. We also know that these changes are complex and that they progress in many tissues. As yet, no one has found one simple, unitary explanation, although the effort to do so has engendered great speculations.

This project intends to develop methods that will provide a new approach to investigating the molecular details of the aging process in multiple cell types, whether they represent cells of the immune system, liver, kidney, muscle or indeed, almost any cell type that can be cultured in the laboratory. The basic strategy relies on the idea that if we grow cells in culture, induce mutations that alter individual aspects of the aging process, select the cells that now behave differently, and then identify which genes were altered, we can begin to identify the key molecular players in the aging process. But achieving that goal first requires that we develop several new technologies; in particular we need better ways of creating mutations and then identifying which genes were altered.

Enter interfering RNA, better known to the research community as RNAi. There are as many possible versions of RNAi as there are genes, each one capable of suppressing the activity of its counterpart gene, and only that gene, if we do it right. Think of them as gene specific bullets. But doing it right, which means using long RNAi molecules to increase their specificity of action, introduces a new problem. Cells can’t distinguish these long molecules from an invading virus, think they are infected and promptly, heroically, commit suicide to prevent the spread of the virus to the rest of our body. It’s called an interferon response. So our strategy is to add to cells a DNA molecule that can serve as the template for making these long RNAs inside the nucleus of the cell, and then arrange to have the newly made RNAs cut into small pieces of the right size inside the nucleus (think of them as shotgun pellets) so that when they are exported to the rest of the cell they are too small to be seen as an invading virus but still able to do their job. If we have a measure of cellular aging, such as the formation of intracellular bodies called autolysosomes, we can expose cells to an enormous collection of RNAi molecules, one molecule at a time, a sufficient variety to suppress every gene there is, select the cells with altered autolysosome formation, and then determine which particular RNAi bullet did it. Since our bullets are tagged for the gene they hit, we now know the culprit.

Our task now is converting this idea to reality. Can we make it work in practice as well as in theory? It won’t be easy, but thanks to the generosity of The Ellison Medical Foundation, the possibility is now there.


DNA Damage and Aging: Dissecting the Genetic Basis of Aging as a Complex Trait
Kevin D. Mills, Assistant Professor, The Jackson Laboratory
2006 New Scholar Award in Aging

The DNA damage theory of aging states that accumulation of DNA damage or chromosomal abnormalities over time can lead to decreasing cell function, and that the additive effects of such damage result in aging. This theory has been partially tested using mouse as an experimental system, where mouse strains with engineered deficiencies in DNA repair often show some signs of accelerated aging. However, natural aging and age-specific diseases, such as cancer, are complex and variable phenomena. I propose to investigate the connection between DNA damage and natural variations in aging. In this regard we will exploit a unique collection of aging inbred mouse strains available at The Jackson Laboratory. This strain collection, developed and maintained, in part with the help of The Ellison Foundation funding, comprises 32 strains of well-characterized, genetically defined young, middle age, and old mice. This extraordinary resource will afford us the opportunity to investigate the genetic bases for natural variability in DNA repair and to test the extent to which this influences aging and age-associated diseases. We will conduct a comprehensive survey of this strain collection to measure changes in DNA repair proficiency with increasing age, and then determine whether DNA repair processes are affected by the genetic variation between strains. These studies are significant because they will begin to dissect the genetic basis of natural aging. In addition, our findings may have important implications for understanding individual variations in the susceptibility to specific age related diseases. As cancer is a major age associated disease in both humans and mice, this proposal has major potential to illuminate the mechanisms underlying the connection between cancer and aging.