My name is Tori Lazerson, and I am a bioengineering major at the University of California, San Diego. I have been involved with research on cardiac extracellular matrix hydrogels at the Christman Lab at UC San Diego for the past two and a half years. I also conducted research on the development of a tumor-derived extracellular matrix hydrogel at Lawrence Livermore National Laboratory in the summer of 2018. This summer, I have had the opportunity to work in the Andersen Lab at the Buck Institute for Research on Aging under the direction of Dr. Julie Andersen and Dr. Chaska Walton. The focus of the Andersen Lab is to uncover the underlying processes that drive age-related neurodegenerative diseases in order to develop novel therapeutics to slow or prevent them. A potential target for such therapeutics is senescent cells, which have been linked to many diseases of aging. Senescence is commonly known as a state of permanent withdrawal from the cell cycle in response to persistent DNA damage.

The goal of my project is to determine whether senescence in neurons and astrocytes, two of the main cell types in the brain, plays a role in Alzheimer’s Disease. The main method of investigation involves exposing mixed cultures of neurons and astrocytes to amyloid beta, a peptide that aggregates into plaques in the brains of Alzheimer’s patients, and quantifying various senescence markers to determine whether or not the cells become senescent. The issue of neuronal senescence is particularly important because neurons have long been considered post-mitotic because they do not proliferate and, therefore, incapable of reaching a senescent state. However, it has recently been shown that neurons are capable of undergoing complete cell division, which indicates that they may be capable of senescence. The investigation of senescence as a possible mechanism for Alzheimer’s Disease could lead to the development of a novel therapeutic to slow, stop, or reverse the disease progression. This is particularly important since drugs designed to clear amyloid beta from the brain have so far failed to demonstrate significant cognitive improvement in clinical trials. If the mechanism of action of Alzheimer’s Disease is linked to senescence, then this discovery could lead to a new approach for developing therapeutics that could significantly benefit the millions of people and families affected by this devastating disease.

Through the SENS Research Foundation Summer Scholars Program, I worked in Dr. Jennifer Garrison’s lab at the Buck Institute for Research on Aging. The Garrison Lab uses the nematode worm C. elegans and mouse models to investigate cellular and circuit mechanisms of neuropeptide signaling and how they may change with age. Neuropeptides are secreted molecules that facilitate long-distance communication between neurons and between the brain and periphery, acting like the brain’s wifi.

Intermediate filaments (IFs) are one of the three cytoskeletal systems. They are found and play important roles in nearly all cells in vertebrates and have been implicated in disease and aging. Several diseases are associated with mutations in IF proteins, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Hutchinson-Gilford progeria syndrome, and dominant cataracts. We are particularly interested in the intermediate filament vimentin. Previous studies in in vitro and in vivo mouse models suggest that vimentin is involved in proteostasis (protein regulation), stress response, and aging, and that loss of vimentin may confer negative consequences in situations of stress and possibly aging.

Accordingly, I will use C. elegans to investigate the role of vimentin in stress and aging in vivo. C. elegans provide an ideal system to do so with a short lifespan, ease of genetic manipulation, and several stress-inducing paradigms. C. elegans have 11 intermediate filament genes, and very little is known about the role of intermediate filaments in C. elegans. We have obtained mutant C. elegans strains for each of five vimentin candidate intermediate filament genes. Using these strains, I plan to: (1) investigate the role intermediate filaments play in stress; (2) examine how intermediate filaments are involved in aging; and (3) identify a vimentin homolog in C. elegans for future studies. Future studies of a vimentin homolog in C. elegans may elucidate the role of intermediate filaments in age-related diseases involving protein aggregation, such as Parkinson’s Disease, Alzheimer’s Disease, and Huntington’s Disease.