Investigating Cellular Senescence at the Single Cell Level

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Project Summary/Abstract Aging is a key risk factor for chronic disease development which can affect lifespan and quality of life. Cellular senescence has emerged as a potential target to slow down the aging process. Senescent cells are in a state of proliferative arrest and are highly associated with aging and pathological conditions. They accumulate in multiple tissues and secrete pro-inflammatory cytokines and other kinds of molecules that damage surrounding tissues. The markers p16 and p21 (cyclin dependent kinase inhibitors) are commonly used to identify senescent cells, but emerging evidence has shown that these markers are not entirely sensitive or specific markers for senescence. There is currently a lack of understanding of the exact genetic markers that define senescent cells especially on the single cell level. With studies showing that senescent cell clearance can alleviate various diseases associated with aging it is vital to achieve a greater understanding of senescent cell markers so that precision medicine treatments can be designed to more effectively eliminate senescent cells. In this proposal we aim to examine the transcriptome of senescent cells on the single cell level both with aging and senolytic treatment in human adipose tissues. Senescent cells have been demonstrated to accumulate in adipose tissue with aging and chronic disease and with the vast array of cell types present in adipose tissue it makes an excellent model to study specific cell types and markers associated with senescence. Aim 1 will explore the transcriptome of naturally occurring senescent cell populations in adipose tissue with aging. We will use single nucleus RNA sequencing to capture cell types sensitive to typical single cell dissociation methods and compare the transcriptome differences between cells in aged vs. young tissues. We hypothesize that adipose tissue from older donors will contain more senescent cells and that several novel genetic markers will be identified in these cells. Aim 2 will look at the effects of senolytic treatment on human adipose tissue on the single cell level. Senolytics are drugs that are designed to specifically eliminate senescent cells but we do not know the precise cell types targeted by senolytics. We will use single nucleus RNA sequencing to uncover the transcriptome changes that occur with senescent cell elimination and learn what cell types are removed with senolytic treatment. This project will help advance the field achieving a greater understanding of senescent cell populations in adipose tissue and the markers that define them, which is essential to understanding and potentially treating numerous diseases. Through this fellowship my training will include developing my skills in genetics, aging, computational analysis, communication, presentation, networking, scientific writing, clinical knowledge and mentorship. This training will occur in the environment of UCONN Health as well as the Jackson Laboratory and other research institutions. This work will allow me to take advantage of training opportunities and mentorship to advance my career as a future physician-scientist.