Oxidative Stress Induced Senescence Gives Rise to Transcriptionally Distinct Physiological States

Abstract

As people age, the risk of cardiovascular disease, diabetes, cancer, and Alzheimers disease increases, making age itself the greatest risk factor for many human diseases. Thus, understanding the aging process can have profound consequences for human health. One striking feature of the aging process is the accumulation of senescent cells with age. When cells become damaged, they can enter a state of senescence which is a permanent cell cycle exit associated with the secretion of inflammatory cytokines. In mouse models of aging, the destruction of senescent cells with senolytic drugs delays age-associated decline and extends healthy lifespan. Yet, despite the wealth of accumulated knowledge, we do not entirely understand the biology of senescent cells. Prior work has shown that senescence is associated with increased variation in gene expression, suggesting that there may exist distinct transcriptional signatures of senescence. Understanding the different transcriptional physiological states of senescent cells would allow us to better treat them with cell-type-specific senolytic drugs. Here, we performed large-scale single-cell RNA-sequencing time series experiments to understand the development of transcriptional heterogeneity among senescent cell types. Our approach allowed us to observe and classify different transcriptional signatures of senescent cells as they emerged through time. We found that upon entering oxidative stress-induced senescence, separate subpopulations of cells were reproducibly adopting two distinct transcriptional states, one of which was associated with stress response and the second one with tissue remodeling. Our data suggest that a combination of senolytic drugs may be needed to more effectively eliminate senescent cells by targeting physiologically distinct sub-populations.