DNA repair and anti-cancer mechanisms in the longest-living mammal: the bowhead whale

The bowhead whale, which lives for over 200 years and has a low cancer rate despite its large size, relies on highly efficient and accurate DNA repair for maintaining genome integrity. Notably, it doesn't have additional tumor suppressor genes as previously thought. The study identifies two proteins, CIRBP and RPA2, contributing to this efficient DNA repair, which may offer insights into developing longevity and cancer prevention mechanisms in humans.

This study proposes a new theory of biological systemic ageing centered on the role of epigenetic changes, particularly DNA methylation, in ageing processes. Researchers observed that certain classes of CpG DNA methylation loci demonstrate a variance increase correlated with chronological age, suggesting a built-in, unavoidable limitation in the fidelity of the epigenetic system. They propose that this fidelity limitation causes a progressive deregulation, leading to a 'phenotype of age'. A developed deep-learning model, utilizing knowledge of this deregulation, accurately predicts age across species. The study suggests that the inability to maintain perfect fidelity in all epigenetic information results in a feedback cycle of deregulation that accelerates ageing.

Single-cell RNA sequencing was prformed on ovarian tissue from young and reproductively aged mice, revealing significant transcriptomic changes with aging. Notably, there was a doubling of immune cells, especially T and B lymphocytes, and changes in stromal fibroblasts pathways. The follicular cells exhibited increased stress response, immunogenic and fibrotic signaling with age, more in atretic granulosa cells, but also noticeable in healthy granulosa cells. Interestingly, no age-related cellular senescence was observed, raising new hypotheses for mechanisms of ovarian aging.

Using machine learning, the researchers analyzed stemness—the fundamental properties of stem cells—in 17,382 healthy human tissue samples, aged between 20 and 79 years. They found that most tissues showed a significant decrease in stemness as age increased. The exception was the uterus, which showed increased stemness with age. Additionally, there was a general trend of stemness correlating positively with cell proliferation and negatively with cellular senescence. This evidence supports the hypothesis that stem cell deterioration contributes to human aging.