The whale’s remarkable lifespan and low cancer risk stem from a well-coordinated DNA repair system driven by a unique protein, CIRBP. The scientists discovered that this mechanism not only preserves the whale’s genome but can also enhance DNA repair and stability in human cells.
Study: Evidence for enhanced DNA repair in a long-lived bowhead whale. “Bowhead whale close-up” from UW News, CC BY 2.0
In a recent study published in the journal Natureresearchers presented evidence for enhanced 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 cell count, the bowhead whale is not particularly prone to cancer, a discrepancy known as Peto’s paradox. Therefore, it may possess unique genetic mechanisms to prevent cancer and age-related diseases, allowing for a long lifespan. 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 multistep model of carcinogenesis, the transition from a normal to a cancerous cell involves many distinct genetic hits (mutations). Longer-lived and larger species may require a greater number of hits for malignant transformation, given their longer life span and greater cell numbers. Consistently, studies have shown that mouse fibroblasts require two hits, while human fibroblasts require five hits. Therefore, longer-lived and larger organisms may have even more layers of protection than humans.
Molecular and cellular basis of cetacean longevity
In the present study, the researchers presented evidence of molecular and cellular characteristics that may underlie the whale’s longevity and cancer resistance. Most analyzes were performed on primary skin fibroblasts, and generalization to epithelial cancer models requires further investigation.
Telomerase Activity and Cellular Aging
They observed that bowhead whale skin fibroblasts, like human fibroblasts, lacked telomerase activity and showed replicative senescence and telomere shortening during serial passage. Telomerase activity was undetectable in fibroblasts and most tissues, with low levels in the skin. Replicative senescence was prevented in human and whale fibroblasts by overexpression of human telomerase reverse transcriptase (hTERT) to maintain telomere length. Stress-induced senescence was readily observed in whale fibroblasts after γ-irradiation. Transcriptional analysis of senescent cells revealed impaired induction of a 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, without increasing the apoptotic response to genotoxic stress compared to human cells. This contrasts with elephant models that rely on increased p53 signaling and apoptosis for tumor suppression. Next, the team investigated the number of genetic hits required for oncogenic transformation. Human primary fibroblasts expressing hTERT required monkey 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.
On the contrary, hTERT-whale-expressing fibroblasts were transformed with only SV40 LT and HRAS (G12V), suggesting that fewer genetic hits were sufficient for malignant transformation. Mouse xenograft experiments confirmed these transformation results.
Mutation frequency and genome stability
Whole-genome sequencing of tumor xenografts derived from fibroblasts and untransformed parental cells showed comparable relative proportions of single-nucleotide variants (SNV). Notably, whale tumors showed a significantly lower frequency of de novo somatics SNV and reduced number of large structural variants (eg, insertions, duplications, and deletions) and small insertion-deletion mutations (indels), especially among structural variants > 500 kb. Mutagenicity assays showed lower mutation rates in 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. The results were consistent in both SMM-follow and HPRT mutant reporter assays and arc fibroblasts showed higher basal and damage-induced PARP activity.
Comparative DNA repair pathways
The team then 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 mismatch repair efficiency (MMR) from mouse, human or cow fibroblasts. In addition, whale fibroblasts showed a significantly higher frequency of homologous recombination (HR) and non-homologous end connection (NHEJ) repair by cells from other species.
Whale fibroblasts also resolved double helix breaks (DSB) significantly faster than human cells. Further experiments showed that NHEJ Repair in the bowhead whale had a higher fidelity than in humans or other mammals. Post-irradiation micronuclei formation was reduced and large deletions were less frequent in arcuate cells in an endogenous PTEN place, consistent with more accurate NHEJ and overall maintenance of genome stability.
Increased CIRBP expression in bowhead whales
A comparison of DNA repair protein expression in mammals showed a higher abundance of DNA-dependent protein kinase catalytic subunit (DNA-PKcs), Ku70and Ku80 in humans than in other species, including bowhead whales. However, the bowhead whale had a markedly higher abundance of cold-induced RNA-binding protein (CIRBP), which was largely undetected in other mammals. bowhead whale (bwCIRBP) and of man CIRBP (hCIRBP) differ by five amino acids at the C-terminus. Substitution of these amino acids in hCIRBP with bwCIRBP remains increased the abundance of hCIRBPreplacing it bwCIRBP leftovers with hCIRBP the remains reduced it. The authors hypothesize that CIRBP can promote repair by forming protective condensates at sites of DNA damage through liquid-liquid phase separation (LLPS).
Functional role of CIRBP in repair and longevity
Then overexpression bwCIRBP in human cells with built-in reporters increased the frequency of hits HR and NHEJ repair events and decreased indel percentages. However, CIRBP deletion in whale cells significantly increased deletions and decreased HR and NHEJ efficiency. CIRBP also reduced micronucleus formation and promoted terminal protection and DNA repair fidelity through PAR-dependent interactions. Finally, overexpression of hCIRBP and bwCIRBP in Drosophila resulted in a consistent increase in lifespan compared to controls. Overexpression also improved survival after treatment with ionizing radiation, with human and arc transgenes significantly extending lifespan in mixed-effects Cox models.
Conclusions: Fix-not-eliminate strategy for longevity
Bowhead whale fibroblasts require fewer mutant hits for oncogenic transformation than human counterparts. However, whale fibroblasts showed amplified DNA DSB repair capacity and fidelity and lower mutation rates than other mammalian cells. Besides, CIRBP was highly expressed in whale tissues and fibroblasts. bwCIRBP strengthened both HR and NHEJ repair in human cells.
CIRBP overexpression in Drosophila increased lifetime and radiation resistance. Taken together, these findings suggest that bowhead whales maintain genomic integrity rather than relying on additional tumor suppressor genes to prevent tumorigenesis. This repair-not-elimination strategy emphasizes faithful DNA repair over apoptotic clearance and may support the species’ exceptional longevity and resistance to cancer. Importantly, these mechanisms are conserved in all mammals, including humans. Functional experiments showing that the arc CIRBP improves DNA repair efficiency and reduces mutagenicity in human cells suggest possible translational relevance. Reinforcement CIRBP Its activity or mimicking its structural features could enhance genome maintenance in aging human tissues, reduce the accumulation of mutations and potentially delay the onset of age-related diseases and cancer.
What do the naked mole rat and the bowhead whale (lives up to 200 years) have in common to explain their remarkable longevity?
Enhanced DNA repair https://t.co/YqP2E1XePBhttps://t.co/w57FVPj2Cz– Eric Topol (@EricTopol) October 29, 2025
