Aging, Biological Resilience and Neurodegenerative Disease

In the Van Raamsdonk lab, we are interested in the genetics and biology of aging and the pathogenesis of neurodegenerative disease. We are also highly interested in biological resilience and how that contributes to longevity and neurodegeneration. Much of our work focuses on the mitochondria as it highly involved in lifespan, resilience and neurodegenerative disease. To complete these studies, we primarily use a simple genetic model organism, the worm C. elegans. Our work in Geroscience aims to advance our understanding of the molecular mechanisms underlying longevity and resilience and apply that knowledge to promote healthy aging and develop novel treatments for neurodegenerative disease.

Role of biological resilience in aging.
In examining the molecular mechanisms of lifespan extension in long-lived genetic mutants, we have identified a number of stress response pathways that contribute to longevity including the DAF-16-mediated stress response, the mitochondrial unfolded protein response, the p38-mediated innate immune signaling pathway and the mitochondrial thioredoxin system. These pathways also act to increase cellular resilience leading to a significant correlation between these phenotypes. The correlation appears to result from similar genetic pathways contributing to both resilience and longevity. We are continuing to explore the relationship between biological resilience and lifespan and the molecular mechanisms contributing to both.

Geroscience - identifying mechanisms contributing to lifespan-extension and applying these insights to treat neurodegenerative disease.
Our work, and the work of others, indicates that there are specific genetic factors that are required by multiple distinct pathways of lifespan extension. In proof of principle studies, we have identified two of these common downstream mediators of longevity: the FOXO transcription factor DAF-16 and the mitochondrial unfolded protein response transcription factor ATFS-1. In order to identify further common downstream mediators of longevity, we are examining overlapping changes in gene expression among a diverse set of long-lived mutants and defining the contribution of these genes to lifespan extension. We will then examine the ability of identified lifespan-extending pathways to protect against neurodegenerative disease.

Mechanisms of lifespan extension in long-lived genetic mutants of different aging pathways.
In order to better understand the mechanism of lifespan extension in long-lived genetic mutants, we are examining the effects of these mutations on the pillars of aging: stress resistance, proteostasis, metabolism, immune function, epigenetic changes and macromolecular damage. Combined with gene expression data, these results will allow us to look at similarities between mutants as well as the extent to which gene expression patterns correlate with enhancement of the different pillars of aging. We are especially interested in the role of biological resilience.

Novel treatments for neurodegenerative disease that target genetic pathways of aging.
We have previously shown that targeting molecular pathways that have been shown to affect aging can be neuroprotective in C. elegans models of Parkinson's and Huntington's disease. However, it is currently uncertain which pathways of lifespan extension will provide the greatest neuroprotection and thus be the best target to test in mammalian models. Accordingly, we will determine which genetic targets associated with aging are most neuroprotective in C. elegans models of neurodegenerative disease, in order to prioritize future studies in rodent models of disease.

Role of mitochondrial dynamics in biological resilience and longevity.
Our work and the work of others indicates that mitochondrial dynamics play an important role in stress response, disease and longevity. Using a genetic approach, we will determine the molecular mechanisms by which modulation of mitochondrial fission and fusion can enhance resilience and increase lifespan. By using C. elegans as a model organism, we can examine mitochondrial morphology in a whole, live organism that has well defined stress assays and that has been extensively used to study lifespan.

Molecular mechanisms by which a mild elevation of reactive oxygen species (ROS) leads to increased longevity.
We have previously shown that the deletion of the mitochondrial superoxide dismutase gene, sod-2, increases lifespan and that elevated ROS levels are required for the long lifespan of sod-2 mutants. Similarly, directly increasing ROS levels through treatment with the superoxide-generating compound paraquat can also increase lifespan. We are currently working to define the conditions under which ROS can extend longevity and using this information to elucidate the molecular mechanisms involved.

Our Research

Aging, Biological Resilience and Neurodegenerative Disease

Our Support

We would like to thank each of the following funding sources for their support.