It is becoming increasingly evident that metabolism has a pervasive impact on biological systems. Human diseases including heart disease and cancer are defined by abnormal metabolic states, whilst other biological processes considered beneficial to an organism’s health, such as regeneration, require a specific metabolic milieu. The Reznick lab works with a very curious non-model organism, the naked mole-rat which has recently become of great interest in biomedicine due to its extraordinarily long and healthy lifespan (>36 years). Living in arid underground burrows in sub-Saharan Africa with up to 300 animals in a single colony, the naked mole-rat’s environment presents several challenges including low oxygen and high CO2 levels. Given these pressures, the naked mole-rat has evolved various unique features including a remodeled metabolism which we believe imparts protection against environmental and age-related cellular insults like hypoxia and simultaneously promotes a long healthspan.
Our research: The overarching aim of the Reznick lab is to identify evolutionary innovations in the naked mole-rat and subsequently introduce these features into mice to assess their impact on hypoxia tolerance, regeneration as well as other markers of metabolic fitness.
Our goals: Our previous research identified several features of metabolic remodeling in the cardiovascular system of the naked mole-rat which confer protection against extreme hypoxia while contributing to the cardiovascular fitness and long healthspan of this species. We interrogate the genetic, epigenetic, and post-translational basis of the naked mole-rat’s rewired metabolism in order to understand the molecular, and environmental cues which establish their metabolic program. With insights from the naked mole-rat, we also explore ways to tweak metabolism in mouse models in order to protect their tissues against hypoxia and aging-related cellular insults. For example, we have previously identified that enhanced fructose metabolism in the naked mole-rat is protective against hypoxia. We are now exploring whether enhancing the ability to metabolize fructose in organs effected by ischaemia (eg. heart and brain) can protect mice against acute ischaemic episodes.
We have also found that naked mole-rat metabolism has fetal-like features which are maintained into adulthood. Our lab aims to understand the regulation and significance of maintaining a neotenous program in an adult animal. Furthermore, we’re interested in the implications of a neotenous program for ageing-related diseases with a focus on regenerative capacities in the heart after myocardial infarction.
Our successes: Jane Reznick and colleagues discovered that naked mole-rats can survive up to 18 minutes in 0% oxygen by switching to fructose-dependent glycolysis in several tissues. We have since examined the metabolism of the naked mole-rat further and identified several other novel metabolic adaptations which are protective in the context of hypoxia. The Reznick lab will use these previous findings as a springboard for further exploration of metabolic adaptations and their relevance in mouse models of age-related diseases.
Our methods/techniques: We use a non-standard animal model the naked mole-rat and transgenic mouse models to explore metabolic adaptations to severe hypoxic and ischaemic events with a focus on the cardiovascular system. An interdisciplinary approach comprised of in vivo physiology, molecular and biochemistry techniques as well omics technologies are used to asses metabolic adaptations and their contribution to the cardiovascular system in diseased and hypoxic states.
Figure A: Naked mole-rats are eusocial mammals with an extremely long lifespan (>36 years) (Photo: Colin Lewin)
Figure B: Naked mole rats release fructose into their circulation and metabolize it in their tissues in order to survive bouts of extreme hypoxia. Fructose content in the blood under normoxia (N) and anoxia (A) in the mouse (white) and naked mole-rat (green)
Figure C: Expression of fructose specific transporter GLUT5 is ubiquitously and highly expressed in naked mole-rat tissues. This is just one example of rewired metabolism in the naked mole-rat.
Figure D: Metabolic reprogramming at the transcriptional level allows the naked mole-rat heart to utilize fructose and maintain heart function in contrast to mouse heart which declines in function when glucose is exchanged for fructose.