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Insights on Aging: The Role of Replication Stress

Replication stress refers to the slowing or stalling of replication fork progression during DNA synthesis. Exciting new research highlights how replication stress is a key driver of cellular senescence and aging. This stress disrupts the faithful copying of the genome, linking it to various hereditary disorders that accelerate aging.

Key Takeaways:

  • Replication Fork Stalling: Various endogenous and exogenous factors can cause the replication fork to stall during DNA replication. This stalling prevents the complete and accurate copying of the genome, leading to DNA damage. Fork stalling and collapse contribute significantly to genomic instability, a hallmark of aging.

  • Telomere Attrition: Replication stress can cause difficulties in replicating chromosome ends, leading to telomere attrition or telomeric DNA damage. Telomeres are protective structures at the ends of chromosomes, and their erosion is associated with cellular aging. Disruption of the shelterin complex, which protects telomeres, further accelerates cellular senescence.

  • Stem Cell Decline: Replication stress depletes the reservoir of stem cells by driving them into senescence or apoptosis. This loss of functional stem cells impairs the regenerative capacity of tissues and organs, contributing to age-related decline. For example, replication stress impacts hematopoietic stem cells, leading to a decline in blood cell production.

  • Double-Strand Breaks (DSBs): Inducible DSBs, which are highly toxic DNA lesions, are linked to cellular senescence and apoptosis. These breaks can activate the senescence-associated secretory phenotype (SASP), a pro-inflammatory state that influences neighboring cells and contributes to tissue aging.

  • Epigenetic Changes: Replication stress can induce abnormal epigenetic regulation, affecting gene transcription and histone recycling. Changes in chromatin state can lead to sustained inflammatory responses and further genomic instability. These epigenetic changes are associated with age-related phenotypes and diseases.

  • Mitochondrial Dysfunction: Replication stress in mitochondria compromises their function, reducing energy production and increasing cellular frailty. Mitochondrial DNA damage and the release of DNA fragments into the cytosol can trigger inflammatory responses via the cGAS-STING pathway, exacerbating aging.

  • Cellular Senescence Pathways: Replication stress activates various cellular pathways that lead to senescence. For example, stalled replication forks can trigger the ATR-Chk1 signaling pathway, leading to cell cycle arrest. Chronic activation of these pathways results in permanent cell cycle exit and the accumulation of senescent cells.

  • Senotherapeutic Approaches: Understanding the mechanisms by which replication stress drives aging opens the door to potential therapies. Senotherapeutics aim to clear senescent cells or modulate the pathways activated by replication stress to delay aging and treat age-related diseases.

This comprehensive view of how replication stress influences aging underscores the importance of maintaining genomic stability and proper replication mechanisms to promote healthy aging and prevent age-related diseases.

Herr, L.M., et al., Replication stress as a driver of cellular senescence and aging. Communications Biology, 2024. 7(1): p. 616.

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