The Naked Mole Rat's Longevity and DNA Repair Mechanisms

The naked mole rat (Heterocephalus glaber), native to East Africa, is renowned for its remarkable longevity, living up to 37 years, almost 10 times longer than other mammals of similar size. This unusual lifespan has intrigued scientists, who attribute it to unique adaptations that maintain DNA integrity.

DNA Damage and Repair in Ageing

• As organisms age, DNA damage accumulates, leading to genomic instability and diseases.
• DNA repair is crucial, involving several molecular pathways.
• Errors in these pathways increase the risk of ageing and cancer.

The Role of Cyclic GMP-AMP Synthase (cGAS)

• cGAS Function: In humans and mice, cGAS detects foreign DNA and triggers immune responses but also suppresses homologous recombination, a key DNA repair system.
• This suppression can enhance cellular ageing and cancer risk.

Research Findings on Naked Mole Rats

A study led by Tongji University, published in Science, explored if naked mole rats have evolved a different cGAS functionality that supports DNA repair rather than harming it.

• Comparative analysis of cGAS genes and proteins between naked mole rats, humans, and mice.
• Use of genetic engineering to switch amino acids between species to study effects on DNA repair.
• Experiments in cell cultures, fruit flies, and mice tested effects on genome stability and cellular ageing.

Key Discoveries

• In naked mole rats, cGAS enhances homologous recombination, unlike in humans and mice where it interferes.
• This enhancement results from four specific amino acid substitutions in the cGAS structure.
• These changes allow cGAS to bind DNA longer after damage, preventing its destruction and facilitating repair protein interaction.

Implications for Longevity and Age-related Research

• The findings provide a molecular basis for the naked mole rat's longevity and suggest potential pathways for age-related therapies.
• If scientists can replicate these effects in humans, it may lead to new treatments for maintaining genome integrity.
• Medicines targeting cGAS-DNA interactions could enhance DNA repair without compromising the immune system.

The study underscores the potential of evolutionary adaptations in extending lifespan and offers promising avenues for future research in ageing and therapeutic interventions.