Replication stress as a driver of cellular senescence and aging.

Replication stress refers to slowing or stalling of replication fork progression during DNA synthesis that disrupts faithful copying of the genome. While long considered a nexus for DNA damage, the role of replication stress in aging is under-appreciated. The consequential role of replication stress in promotion of organismal aging phenotypes is evidenced by an extensive list of hereditary accelerated aging disorders marked by molecular defects in factors that promote replication fork progression and operate uniquely in the replication stress response. Additionally, recent studies have revealed cellular pathways and phenotypes elicited by replication stress that align with designated hallmarks of aging. Here we review recent advances demonstrating the role of replication stress as an ultimate driver of cellular senescence and aging. We discuss clinical implications of the intriguing links between cellular senescence and aging including application of senotherapeutic approaches in the context of replication stress.

Frontiers in aging special issue: DNA repair and interventions in aging perspective on "loss of epigenetic information as a cause of mammalian aging".

The recently published article in Cell by the Sinclair lab and collaborators entitled "Loss of Epigenetic Information as a Cause of Mammalian Aging" [1] implicates heritable changes in gene expression as the basis for aging, a postulate consistent with the emerging information theory of aging. Sinclair's group and colleagues induced epigenetic changes, i.e., DNA and histone modifications, via double-strand breaks (DSBs) catalyzed by the I-Pol endonuclease at specific genomic loci. The genomic DNA breaks, introduced without inducing insertion or deletion mutations (indels) in a mouse model, were targeted to 19 non-coding regions and one region in ribosomal DNA (rDNA), the latter shown to not have a significant effect on the function or transcription of rDNA [1]. With that experimental model in place, the authors present experimental evidence supporting a model that epigenetic changes drive aging via this inducible DNA break mechanism. After demonstrating the phenotypic alterations of this accelerated aging, they attempt to reverse selective phenotypes by resetting the altered epigenetic landscape. Establishing a causal relationship between epigenetic changes and aging, and how this connection might be manipulated to overturn cellular features of aging, is provocative and merits further study.