Rapid emergence of transcriptional heterogeneity upon molecular stress predisposes cells to two distinct states of senescence.

Slowing aging can reduce the risk of chronic diseases. In particular, eliminating senescent cells is a promising approach to slow aging. Previous studies found that both cells from older animals and senescent cells have noisy gene expression. Here, we performed a large-scale single-cell RNA-sequencing time course to understand how transcriptional heterogeneity develops among senescent cells. We found that cells experiencing senescence-inducing oxidative stress rapidly adopt one of two major transcriptional states. One senescent cell state is associated with stress response, and the other is associated with tissue remodeling. We did not observe increased stochastic gene expression. This data is consistent with the idea that reproducible, limited, distinct, and coherent transcriptional states exist in senescent cell populations. These physiologically distinct senescent cell subtypes may each affect the aging process in unique ways and constitute a source of heterogeneity in aging.