Genome Aging in Women: Hematopoietic Loss of X Chromosome as An Exemplar

Genome aging refers to age‐related acquisition and expansion of de novo mutations in somatic cells, and is now increasingly viewed as a central driver of organismal aging. Loss of X chromosome (LOX), the state in which one X chromosome (ChrX) is missing, represents the most common genetically inferred type of acquired mutation in women. Recent technological advancements, along with the growing availability of large‐scale cohorts for association studies, have provided powerful new insights into this phenomenon. The frequency and clone size of LOX increase significantly with age: with over 10% of women aged 55 years or older showing detectable LOX in blood. LOX preferentially affects the inactivated ChrX derived from either parent, or in some cases, affects the ChrX from one specific parent. Besides aging, the acquisition and expansion of LOX are shaped by factors related to ChrX itself, genome‐wide inherited and acquired variants, and lifestyle and environmental stressors. Due to the critical biological roles of ChrX, even in its inactive state, LOX impairs cellular functions and is strongly linked to hematological malignancies and a range of benign diseases. Understanding the mechanisms driving the causes and consequences of LOX may expand the sex‐biased genomic architecture of aging and uncover strategies for disease prevention in women. In this review, by integrating the most recent progress in LOX studies with unique biology of ChrX and perspectives from aneuploidy, we provide a synthesized and updated understanding of the rise, expansion and consequences of blood LOX, while also posing key questions for future research.