These East African rodents usually live to over 30 years old – an almost unbelievable age for animals of their size. During this time, they very rarely experience heart disease or cancer. In addition, they can go without oxygen for almost twenty minutes without suffering any brain damage at all. For comparison, the brain of a mouse is irreparably destroyed after just one minute of oxygen deprivation, and without sophisticated training, humans can generally only hold their breath for two or three minutes.
Understanding the evolutionary strategies that led to the naked mole rat’s remarkable traits is one of the main research goals being pursued by Australian scientist Dr. Jane Reznick, who has been investigating the metabolism of these rodents in Professor Gary Lewin’s MDC research group on the Molecular Physiology of Somatic Sensation since 2011. Reznick hopes that one day her studies will also benefit humans.
A helping hand to get off the ground
Reznick attracted particular attention with a publication that appeared two years ago in the journal Science. Together with an international team of 25 colleagues, including many from the MDC, the scientist had discovered what metabolic tricks naked mole rats use to combat a prolonged lack of oxygen – which is quite a common problem for these rodents. The animals live in complex systems of burrows in the dry grasslands of East Africa. They usually sleep all together in a heap, and air can become scarce for the animals on the bottom of the pile.
For her innovative research plans based on this study, the 37-year-old molecular biologist has now been awarded one of the coveted Starting Grants of the European Research Council (ERC). The aim of this grant is to support young and promising researchers who want to start an independent career and set up their own research group. Over the next five years, the ERC will provide Reznick with a total of 1.55 million euros for this purpose. She will leave the MDC to start her own group.
Hearts that run on fructose when oxygen is scarce
“Oxygen deficiency in the body or individual organs, also known as hypoxia, is a key factor in many cardiovascular problems, for example, heart attacks or strokes,” explains Reznick. Hypoxia is also often a characteristic feature in malignant tumors. “If we can better understand the metabolic adaptations of the naked mole rat, we might be able to explain why the animals are so well protected against cardiovascular diseases and cancer – and why they can live to be so old,” says Reznick.
In her 2017 study, the researcher was already able to show that the metabolism of a naked mole rat changes when their body lacks oxygen: the animals stop metabolizing glucose, and start using fructose instead. This ability has never before been observed in any other animal, let alone humans; most mammals can only metabolize fructose in two organs: the liver and the kidney.
In addition, Reznick investigated which genes become particularly active in the naked mole rats during the switch from glucose to fructose metabolism. “One of my next steps is to ‘switch on’ these genes in mice,” she says. “My hope is that these animals will then also display higher levels of protection against the dangerous consequences of oxygen deficiency.” If this is the case, it might also be possible to develop similar therapies for humans.
Protection against the consequences of a heart attack
Reznick believes it is possible that one day we might be able to switch the human metabolism in the heart and brain to fructose. “Perhaps such a mechanism already exists and is simply dormant,” speculates the researcher. “If so, it could probably be reactivated.” This could perhaps prevent the often tragic consequences of a heart attack or a stroke. “Both these diseases are accompanied by a lack of oxygen – and consequently energy – reaching the affected organ,” explains Reznick.
The switch from glucose to fructose metabolism is only one strategy employed by the naked mole rat that Reznick discovered. “We now know of other metabolic tricks that the animal uses when oxygen becomes scarce,” says the scientist. “And it would seem these strategies contribute to the extraordinary health and longevity of naked mole rats.” Over the coming years, Reznick hopes to find out which genes and signaling pathways are involved in these strategies. “It is possible that several such mechanisms are also present in humans and are simply lying dormant,” she says. “If we could switch them on, we would probably be able to prevent a large number of cardiovascular diseases – which are unfortunately becoming more common as we live longer lives.”
The MDC researcher’s plans were certainly convincing enough for the ERC. “The naked mole rat has only been studied in very few laboratories worldwide, but it is definitely able to give us a better understanding of the metabolic adaptations that help a living being survive oxygen deficiency for a certain period of time,” she says. “There is no way this would be possible with mice or other model organisms that don’t have the same tricks up their sleeves as mole rats.”
ERC Starting Grants for promising young researchers
ERC Starting Grants are awarded to early-career researchers of any nationality with two to seven years of experience since completion of the PhD (or equivalent degree) and a scientific track record showing great promise. The research must be conducted in a public or private research organisation located in one of the EU Member States or Associated Countries. The funding (maximum €2.5 million per grant, including up to €1 million to cover extraordinary costs) is provided for up to five years. This year, 408 scientists will receive the funding.
Text: Anke Brodmerkel, video: Felix Petermann.
Max Delbrück Center for Molecular Medicine
Phone: +49 30 9406 2121