Mary Gates Endowment For Students

Varuna Ravi

Mary Gates Research Scholar, Winter 2022 & Autumn 2022

Research Project: Investigating the effects of liver senescence and senolytic therapies on age-associated inflammation in SAMP8 mice

Project Description: Cellular senescence is a hallmark of aging that is characterized by irreversible cell cycle arrest and a senescence-associated secretory phenotype. Senescence likely contributes to neurodegenerative diseases like Alzheimer’s disease (AD), and drugs that selectively eliminate senescent cells (senolytics) are currently in clinical trials for AD. Senolytics eliminate senescent cells throughout the body, and it is unclear whether cognitive improvement with senolytics is exclusively due to the elimination of senescent cells in the brain. My preliminary data shows that in the SAMP8 mouse model of AD senolytic treatment of dasatinib plus quercetin (D+Q) improves senescence in the liver-an organ that contributes to systemic and neuroinflammation with aging by secreting pro-inflammatory factors into the blood. I hypothesize that cellular senescence in the liver contributes to age-associated central nervous system dysfunction in SAMP8 mice by increasing inflammatory proteins in the blood, which could then contribute to neuroinflammation through interactions with the brain’s blood vessels. Using tissues from SAMP8 mice that previously underwent senolytic treatment with D+Q or vehicle control, I will investigate whether treatment improved aspects of the aging phenotype of the liver by measuring mRNA and protein levels of aging markers (Aim 1) and whether reduced senescence in the liver is associated with lower levels of inflammatory proteins in the blood using a multiplex cytokine ELISA (Aim 2). Sirtuin-1, serum amyloid A, and cathepsin B levels will be measured using qPCR and Western blotting in Aim 1. In parallel, I will quantify general markers of liver inflammation including pro-inflammatory cytokines and serum amyloid A. This work will provide important insight on whether D+Q is indirectly neuroprotective by improving functions of peripheral organs. The drug D+Q is currently in clinical trials, highlighting the importance of studying how this drug affects the brain and peripheral organs.

What have you learned throughout your research project?

My experience in research has allowed me to expand my understanding of who gets to participate in research and begin to build self efficacy. As someone who majored in Public Health, this project focused on Neuroscience allowed me to tackle a field that I previously thought to be too challenging for me to enter.

It has also showed me that finding mentors who support my identities in and outside of the lab are highly important. Being able to reach out to mentors when you make a mistake or when you would like to apply to scholarships like this one is critical.

What piece of advice do you have for future applicants?

My advice is to get involved in research at any capacity and as early as you can. I have learned so much about myself through research and this experience has shown me what I am capable of. Even if you are just starting out your research, you can apply for scholarships! Don’t wait to apply because 5k is a lot of money!

When applying, make sure you tie your identity into your research. Why did this specific opportunity stick out to you? If you would like someone to read over your essay feel free to reach out!