Replication stress responses in human lymphocytes change sex-specifically during aging

Area of Science:

• Genomics
• Aging Research
• Cellular Biology

Background:

• Aging is associated with increased disease incidence and a gender gap in life expectancy, suggesting sex-specific aging processes.
• Genomic instability is a critical factor in aging, but sex-specific differences remain poorly understood.

Purpose of the Study:

• To investigate sex-specific differences in DNA damage responses (DDRs) and replication stress during aging.
• To identify molecular mechanisms underlying genomic instability in aging males and females.

Main Methods:

• Analysis of DNA damage responses (DDRs) in peripheral blood lymphocytes (PBL) and hematopoietic stem and progenitor cells (HSPC) from male and female donors of varying ages.
• Transcriptomic analysis to identify sex-dependent expression changes in DDR pathways.
• Functional assays including replication dynamics, PCNA ubiquitination, translesion synthesis (TLS)-polymerase activity, and sensitivity to TLS-polymerase inhibitors.

Main Results:

• Transcriptomics revealed significant sex-dependent age-related changes in DDR pathways. Men showed upregulation of DNA repair and replication fork remodeling components.
• Older women displayed reduced activity in the Fanconi anemia pathway, indicating a shift towards translesion synthesis (TLS) for replication stress.
• Older men's PBL showed high dependence on PARP activity, despite unaltered replication dynamics and reduced replication stress.

Conclusions:

• Distinct sex-specific strategies for coping with replication stress emerge in aging individuals.
• Women may employ DNA damage tolerance pathway switching, while men rely on PARP activation.
• These sex-specific mechanisms differentially contribute to the age-related decline in genomic stability.