Fig. 2: Relationships of replication stress to hallmarks of aging.

Evidence from the literature suggests that many of the previously described hallmarks of aging¹⁰⁹ are driven by replication stress. Representative examples are cited below as well as in the text. Chronic Inflammation. Innate immune response activation by LINE-1 element derepression and cytosolic ssDNA incurred by replication stress promotes senescence induction and contributes to sterile inflammation^112,257. Genomic Instability. Replicative stress incurs DNA damage in the form of chromosomal aberrations and DSBs that attenuate replicative lifespan of cells and induce aging-associated tissue dysfunction^9,121,123. Telomere Attrition. Telomeres are fragile sites with DNA sequences prone to form G4 and T-loop secondary structures that break under conditions of replication stress, inducing telomere shortening that limits replicative potential^133,134,139. Stem Cell Exhaustion. Replicative stress in SCs impairs the ability to produce SC progeny. Specific to HSCs, this leads to a variety of tissue-based and organismal dysfunctions including clonal drift and SC attrition^147,151,258. Epigenetic Alterations. Replicative stress recruits a variety of proteins to the stalled replication fork that are involved in remodeling the DNA modification and histone landscapes around the stress. These changes can have long-term effects for cellular senescence^12,259. Mitochondrial Dysfunction. Replication stress in the mitochondria leading to mtDNA mutations causes a deprivation of resources, culminating in premature aging in a pol γ proofreading mutant mouse model¹⁵⁸. In addition, mtDNA replication errors have consequences for nuclear genome replication and stability, which contribute to aging phenotypes¹⁶. BioRender was used to create the figure.