Single-Cell Analysis Reveals Key Factors in Senescence Initiation and Progression

Researchers from the National Institute on Aging have published a new study in Aging using single-cell transcriptomic analysis to identify the specific populations and dynamic transition states during senescence initiation and progression.

Senescence, a state of enduring growth arrest triggered by sublethal cell damage, is known to cause many age-related diseases due to senescent cells secreting proinflammatory and matrix-remodeling proteins that accumulate in the tissues of older individuals. Despite intense interest in identifying robust markers of senescence, the highly heterogeneous and dynamic nature of the senescent phenotype has made this task difficult.

The team performed single-cell RNA-sequencing analysis to document the diverse transcriptomes of human senescent fibroblasts at an individual-cell scale. They characterized the different cell states in cultures undergoing senescence triggered by various stresses. In doing so, the scientists found distinct cell subpopulations that expressed mRNAs encoding proteins with roles in growth arrest, survival, and the secretory phenotype.

They also characterized the dynamic changes in the cells' transcriptomes as they developed etoposide-induced senescence and found two different senescence programs that developed divergently, one in which cells expressed traditional senescence markers such as p16 (CDKN2A) mRNA and another in which cells expressed long noncoding RNAs and splicing was dysregulated. The proliferation status at the time of senescence initiation affected the path of senescence, as determined based on the expressed RNAs.

This deeper understanding of the transcriptomes during the progression of different senescent cell phenotypes will help develop more effective interventions directed at this detrimental cell population. Senescence-associated secretory phenotype (SASP) is a key driver of chronic inflammation in the elderly population, and thus therapeutic interventions directed at removing or inhibiting senescent cells in vivo have the potential to alleviate aging-associated inflammation and improve tissue function.

The study's results provide an individual-cell view of senescence and highlight senescent cells' complex and dynamic nature. Future research should focus on elucidating the functional consequences of the different senescence programs, including the distinct transcriptional regulation of long noncoding RNAs (lncRNAs) and alternative splicing events. These insights will be essential for developing effective therapeutic interventions to combat the effects of senescence.