What Naked Mole-Rats can Tell Us About Gene Splicing, Senescence, and Longevity

Naked mole-rats are rodents that live in subterranian colonies. They have an unusually long lifespan: typically 20 years or longer, while similarly sized rodents live for 3-4 years. Many mechanisms have been proposed to explain this longevity, including reduced cellular senescence.

This study investigated the role of alternative DNA splicing – a process by which multiple proteins can be produced from the same gene. Alternative splicing is important in the cellular response to stress, failure of which can lead to senescence.

Not only was splicing factor expression higher in young adult naked mole-rats than in young adult mice, but expression did not appear to decrease with age, contrary to findings in humans. This strengthens the hypothesis that loss of splicing regulation contributes to senescence and ageing, and that targetting relevant pathways could one day be used to prolong human lifespan.

The data presented here are consistent with a model by which the extreme longevity and conserved healthspan characteristic of NMRs may arise from conservation of alternative splicing regulation and maintenance of patterns of AS. This maintained transcriptomic plasticity could then ensure a more robust response to internal and external environmental stressors and avoidance of cellular senescence. These data add weight to the hypothesis that splicing regulation is a key feature in the avoidance of cellular senescence, and provide a potential explanation for the extreme longevity seen in NMRs. In the future, the genes and pathways responsible for maintenance of splicing regulation and molecular stress response may be promising future therapeutic targets for healthspan and lifespan interventions.

Lee, B., Smith, M., Buffenstein, R., & Harries, L. (2020). Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation. Geroscience. doi: 10.1007/s11357-019-00150-7