The bowhead whale’s remarkable lifespan and low cancer risk stem from a finely tuned DNA repair system driven by a unique protein, CIRBP. Scientists found that this mechanism not only preserves the whale’s genome but can also enhance DNA repair and stability in human cells.
Study: Evidence for improved DNA repair in long-lived bowhead whale. “Bowhead Whale Closeup” by UW News, CC BY 2.0
In a recent study published in the journal Nature, researchers presented evidence for improved DNA repair in bowhead whales.
Exceptional Longevity and Cancer Resistance in Bowhead Whales
The bowhead whale can live for > 200 years and exceed 80,000 kg in mass. Despite its long lifespan and large number of cells, the bowhead whale is not highly prone to cancer, an incongruity known as Peto’s paradox. As such, it may possess unique genetic mechanisms to prevent cancer and age-related diseases, allowing for a long life. However, research on the molecular and cellular mechanisms underlying this longevity in bowhead whales is limited.
Genetic Hits and Cancer Risk Across Species
According to the multistage carcinogenesis model, normal-to-cancer cell transition involves several distinct genetic hits (mutations). Longer-living and larger species may require a higher number of hits for malignant transformation, given the greater lifespan and cell number. Consistently, studies have shown that mouse fibroblasts require two hits, while human fibroblasts require five hits. As such, longer-living and larger organisms may have even more layers of protection than humans.
Molecular and Cellular Basis of Whale Longevity
In the present study, researchers presented evidence of molecular and cellular traits that may underlie longevity and cancer resistance in the bowhead whale. Most assays were performed in primary skin fibroblasts, and generalization to epithelial cancer models requires further investigation.
Telomerase Activity and Cellular Senescence
They observed that skin fibroblasts of the bowhead whale, like human fibroblasts, lacked telomerase activity and showed replicative senescence and telomere shortening upon serial passaging. Telomerase activity was undetectable in fibroblasts and in most tissues, with low levels in skin. Replicative senescence was prevented in human and whale fibroblasts by overexpressing human telomerase reverse transcriptase (hTERT) to maintain telomere length. Stress-induced senescence was readily observed in whale fibroblasts following γ-irradiation. Transcriptomic analysis of senescent cells revealed attenuated induction of senescence-associated secretory phenotype (SASP) factors in whale fibroblasts compared to human cells.
Tumor Suppression Pathways and Transformation Resistance
Whale fibroblasts had lower basal p53 activity, with no increase in apoptotic response upon genotoxic stress compared to human cells. This contrasts with elephant models that rely on elevated p53 signaling and apoptosis for tumor suppression. Next, the team investigated the number of genetic hits needed for oncogenic transformation. Human primary fibroblasts expressing hTERT required simian virus (SV40) large T antigen (SV40 LT), SV40 small T antigen (SV40 ST), and HRas proto-oncogene, GTPase (HRAS) G12V mutation [HRAS (G12V)] for malignant transformation.
In contrast, hTERT-expressing whale fibroblasts were transformed with only SV40 LT and HRAS (G12V), suggesting that fewer genetic hits were sufficient for malignant transformation. Mouse xenograft experiments corroborated these transformation results.
Mutation Frequency and Genome Stability
Whole-genome sequencing of human, mouse, and bowhead whale fibroblast-derived tumor xenografts and non-transformed parental cells indicated comparable relative proportions of single-nucleotide variants (SNVs). Notably, whale tumors showed significantly lower frequency of de novo somatic SNVs and reduced numbers of large structural variants (e.g., insertions, duplications, and deletions) and small insertion-deletion mutations (indels), especially among structural variants > 500 kb. Mutagenesis assays indicated lower mutation rates in bowhead whale fibroblasts after treatment with N-ethyl-N-nitrosourea, ethyl methanesulfonate, and 1-methyl-3-nitro-1-nitrosoguanidine, or γ-irradiation than in human fibroblasts. Results were consistent across both SMM-seq and HPRT mutation-reporter assays, and bowhead fibroblasts showed higher basal and damage-induced PARP activity.
Comparative DNA Repair Pathways
Next, the team observed similar nucleotide excision repair (NER) activity between human and whale fibroblasts, as well as a non-significant upward trend in base excision repair (BER) activity in whale cells. Whale fibroblasts had significantly higher efficiency of mismatch repair (MMR) than mouse, human, or cow fibroblasts. Moreover, whale fibroblasts showed substantially higher frequency of homologous recombination (HR) and non-homologous end joining (NHEJ) repair than cells from other species.
Whale fibroblasts also resolved double-strand breaks (DSBs) significantly faster than human cells. Further experiments indicated that NHEJ repair in the bowhead whale had higher fidelity than in humans or other mammals. Micronuclei formation after irradiation was reduced, and large deletions were least frequent in bowhead cells at an endogenous PTEN locus, consistent with more accurate NHEJ and overall genome-stability maintenance.
Elevated CIRBP Expression in Bowhead Whales
A comparison of the expression of DNA-repair proteins across mammals indicated a higher abundance of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Ku70, and Ku80 in humans than in other species, including bowhead whales. However, the bowhead whale had a markedly higher abundance of cold-inducible RNA-binding protein (CIRBP), which was largely undetected in other mammals. Bowhead whale (bwCIRBP) and human CIRBP (hCIRBP) differ by five amino acids at the C-terminal end. Replacing these amino acids in hCIRBP with bwCIRBP residues increased the abundance of hCIRBP, while substituting the bwCIRBP residues with hCIRBP residues decreased it. The authors hypothesize that CIRBP may promote repair by forming protective condensates at DNA-damage sites through liquid–liquid phase separation (LLPS).
Functional Role of CIRBP in Repair and Longevity
Next, overexpressing bwCIRBP in human cells with integrated reporters increased the frequency of successful HR and NHEJ repair events and decreased indel rates. However, CIRBP deletion in whale cells significantly increased deletions and reduced HR and NHEJ efficiency. CIRBP also reduced micronuclei formation and promoted DNA end-protection and repair fidelity via PAR-dependent interactions. Finally, overexpression of hCIRBP and bwCIRBP in Drosophila resulted in a consistent lifespan increase compared to controls. Overexpression also improved survival after treatment with ionizing radiation, with both human and bowhead transgenes significantly extending lifespan in mixed-effects Cox models.
Conclusions: Repair-Not-Eliminate Strategy for Longevity
Bowhead whale fibroblasts require fewer mutational hits for oncogenic transformation than human counterparts. However, whale fibroblasts showed enhanced DNA DSB repair capacity and fidelity and lower mutation rates than cells of other mammals. Moreover, CIRBP was highly expressed in whale tissues and fibroblasts. bwCIRBP enhanced both HR and NHEJ repair in human cells.
CIRBP overexpression in Drosophila increased lifespan and resistance to irradiation. Overall, these findings suggest that bowhead whales maintain genomic integrity rather than relying on additional tumor-suppressor genes to prevent oncogenesis. This “repair-not-eliminate” strategy emphasizes faithful DNA repair over apoptotic clearance and may underpin the species’ exceptional longevity and resistance to cancer. Importantly, these mechanisms are conserved across mammals, including humans. Functional experiments demonstrating that bowhead CIRBP improves DNA repair efficiency and reduces mutagenesis in human cells suggest potential translational relevance. Enhancing CIRBP activity or mimicking its structural features could strengthen genome maintenance in aging human tissues, reduce the accumulation of mutations, and potentially delay the onset of age-related diseases and cancer.