Evidence of sex differences in cellular senescence

Biological sex is a factor in many conditions, including aging, neurodegenerative disease, cancer, and more. For each of these, men and women display distinct differences in disease development and progression. To date, studies on the molecular basis of such differences have largely focused on sex hormones, typically highlighting their neuroprotective benefits. However, new research suggests that cellular senescence may underlie sex differences in both neurological and non-neurological pathologies. Cellular senescence-stable proliferative arrest with a unique pro-inflammatory phenotype-occurs in response to persistent DNA damage signaling, safeguarding against tissue-level consequences of DNA damage (e.g., tumorigenesis). Though critical for maintaining tissue health, senescence has also been implicated in disease. Indeed, senescent cell accumulation occurs in multiple disease contexts, and the elimination of such cells (via senolytic therapies) alleviates associated disease hallmarks. If cell senescence is a driver of pathophysiology, sex differences in cellular senescence may underlie sex-specific disease outcomes. This review summarizes evidence of sex differences in cellular senescence-highlighting findings from both human and animal studies-and briefly discusses the potential relevance of sex chromosome epigenetics and mosaicism. Current studies show that female sex is associated with greater susceptibility to DNA damage and greater likelihood of senescence onset, despite additional evidence that estrogen protects against genotoxic insult and inhibits senescence regulatory proteins. Further studies on sex differences in cellular senescence are needed, both to verify whether findings from animal studies hold true in human contexts and to validate whether senescence manifests differently between men and women following comparable senescence-inducing stimuli.