Fight Aging!

On the one hand, naked mole-rats are most likely long-lived because they live underground, and thus suffer much lower rates of predation than other similarly sized mammals. Lower rates of extrinsic mortality appear to be a necessary prerequisite for the evolution of a longer species life span. On the other hand, living in a low-oxygen environment appears to have spurred the evolution of broad range of adaptations to that environment that incidentally happen to extend species longevity. Today's open access paper covers one aspect of those adaptations, a resistance to ischemia that reduces the harms resulting from the loss of blood flow to important tissues that takes place during events such as a heart attack.

Interestingly, the researchers note differences in tolerance to hypoxia between naked mole-rats and similar species that correlate with a greater exposure to the low-oxygen underground environment. One can imagine interactions over evolutionary time between the characteristics of predation, instinct and willingness to remain underground, tolerance to hypoxia, and life span. Does all this discovery have relevance to human medicine? That remains an open question. Certainly there is considerable enthusiasm for understanding exactly how naked mole-rats are near immune to cancer, and building therapies based upon that understanding. It remains to be seen as to whether this is a practical goal, however.

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles

While data on O2/CO2 levels in wild naked mole-rat (NMR) burrows is limited and has never been measured in a nest chamber full of animals, NMRs in captive colonies are able to tolerate hours of extreme hypoxia (5% O2 for up to 300 minutes), and can even survive up to 18 minutes of anoxia. NMRs often elect to spend more time in areas of their burrow system with extreme atmospheric conditions including the nest chamber, where they may spend up to 70% of their time. This is something not regularly seen in other social African mole-rat species.

This challenging hypoxic habitat creates strong selective pressures and has driven the evolution of unique adaptive traits in NMRs. Mammalian cells are not usually hypoxia-resistant, requiring uninterrupted O2 availability for survival. Fluctuations in O2 availability can lead to ischaemia/reperfusion injury and irreversible organ damage such as is observed following a heart attack. Given the absence of cardiovascular disease in NMRs, despite regular fluctuating exposure to hypoxia/anoxia and normoxia, NMR hearts appear to have evolved resistance to both reduced O2 availability and ischaemia/reperfusion (I/R) injury.

NMR metabolism has unusual features, such as the ability to switch from glucose to fructose-driven glycolysis in the brain during anoxia. However, the mechanisms that underpin the extraordinary physiological adaptation to limited O2 availability in the heart are unknown. To determine how these adaptations arise in NMR, we hypothesised that comparison to other African mole-rat genera would enable us to infer the changes in gene expression and metabolic signatures that contribute to the extreme hypoxia tolerance, resistance to cardiovascular injury, and longevity of NMRs.

To identify the mechanisms behind these exceptional traits, metabolomics, and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57BL/6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57BL/6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span.