Researchers from the Institute of Biochemistry II at the Goethe University Medical Faculty in Frankfurt have identified the accumulation of DNA damage, which triggers chronic inflammation, as one of the causes of premature aging. The authors shared their study findings in the journal Science.
The scientists paid particular attention to the protein SPRTN, which plays a crucial role in maintaining stable genome functionality. Normally, DNA and proteins engage in controlled interactions, but sometimes so-called DNA-protein crosslinks (DPCs) are formed when proteins bind covalently and irreversibly to DNA.
These linkages are particularly toxic to the cell: if they are not promptly removed, they induce DNA damage, impede cell division, and lead to premature aging and early organism death. These processes had previously been observed in mouse experiments.
Previously, researchers assumed that SPRTN could only repair such defects during DNA replication. However, the new work demonstrated that this protein is also activated during mitosis—the cell division stage where chromosomes are segregated. In the absence of SPRTN, cells accumulate toxic compounds and experience chromosome segregation errors, resulting in the formation of micronuclei containing damaged DNA.
The scientists utilized proteomic analysis and CRISPR/Cas9 technology, which helped reveal that unrepaired DPCs stimulate the innate immune pathway cGAS–STING. This pathway traditionally defends the body against viruses, but in this scenario, it provokes chronic inflammation that accelerates aging processes.
Experiments were also conducted on models of a rare hereditary condition—Ruijs-Aalfs progeria syndrome, which is associated with mutations in the SPRTN gene. Rodents with similar abnormalities displayed severe impairments mirroring human disease symptoms. The researchers note that disabling the cGAS–STING pathway prevents premature aging and death in these animals, regardless of whether the mechanism is genetic or drug-induced.
The work’s authors specify that their findings not only explain how DNA defects correlate with aging but also point to potential targets for therapeutic interventions against age-related and analogous pathologies.
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