Low Cancer Incidence in Naked Mole-Rats May Be Related to Their Inability to Express the Warburg Effect

Abstract

Metabolic flexibility in mammals enables stressed tissues to generate additional ATP by converting large amounts of glucose into lactic acid; however, this process can cause transient local or systemic acidosis. Certain mammals are adapted to extreme environments and are capable of enhanced metabolic flexibility as a specialized adaptation to challenging habitat niches. For example, naked mole-rats (NMRs) are a fossorial and hypoxia-tolerant mammal whose metabolic responses to environmental stressors markedly differ from most other mammals. When exposed to hypoxia, NMRs exhibit robust hypometabolism but develop minimal acidosis. Furthermore, and despite a very long lifespan relative to other rodents, NMRs have a remarkably low cancer incidence. Most advanced cancers in mammals display increased production of lactic acid from glucose, irrespective of oxygen availability. This hallmark of cancer is known as the Warburg effect (WE). Most malignancies acquire this metabolic phenotype during their somatic evolution, as the WE benefits tumor growth in several ways. We propose that the peculiar metabolism of the NMR makes development of the WE inherently difficult, which might contribute to the extraordinarily low cancer rate in NMRs. Such an adaptation of NMRs to their subterranean environment may have been facilitated by modified biochemical responses with a stronger inhibition of the production of CO2 and lactic acid by a decreased extracellular pH. Since this pH-inhibition could be deeply hard-wired in their metabolic make-up, it may be difficult for malignant cells in NMRs to acquire the WE-phenotype that facilitates cancer growth in other mammals. In the present commentary, we discuss this idea and propose experimental tests of our hypothesis.

Social touch shapes communication and animal recognition in naked mole-rats

“…Although naked mole-rats have captivated biologists for decades, mainly for their longevity, resilience to cancer, and apparent indifference to certain types of pain (Buffenstein, 2008; Buffenstein et al, 2021; Freire Jorge et al, 2022), the biology of their social interactions has been less studied. Here, we argue that their spontaneous behavior is reflective of their biological caste and rank, and we establish face-to-face contact as a key social behavior—perhaps indispensable for the stability of the naked mole-rats’ reproductive and social hierarchies.…”

Macrophages from naked mole-rat possess distinct immunometabolic signatures upon polarization

“…Aerobic glycolysis is the hallmark of activated immune cells. Interestingly, recent studies of NMR metabolism under hypoxia led to the hypothesis that in most NMR tissues glycolysis and OXPHOS are strongly coupled to avoid either systemic or local lactic acidosis ( 32 ). In agreement with this idea NMR M1 cells lacked acidosis ( Figure 2I ).…”

“…Gene expression analysis suggests that NMR possesses systemic metabolic adaptations: a lower performance of the mitochondrial respiratory chain, the use of fatty acids as the main source for OXPHOS ( 24 ) and the elevated baseline levels of HIF1-α ( 25 ). Unique type of thermoregulation ( 26 – 28 ), resistance to anoxia, hypoxia ( 29 ), hypercapnia ( 30 ) and presence of mild depolarization of mitochondria throughout lifespan ( 31 ), are also important parameters that determine NMR as a species, whose metabolic responses to environmental stress markedly differ from most other mammals ( 32 ). However, the immunometabolic features of NMR macrophages under polarizing stimuli remain unknown.…”

Exposing the naked truth about how mole‐rats evade cancer

“…However, lactic acidosis is extremely limited in naked mole-rats, and this led the researchers to hypothesize that the animals' low cancer incidence may be related to the strong inhibition of lactate production and buildup in their tissues, which thus deprives cancerous cells of a key advantage. 4 "It certainly seems like, big picture, there's something to this high lactate and cancer relationship," says study coauthor Matthew Goodwin, MD, PhD, an assistant professor of orthopedic surgery and neurological surgery at Washington University in St. Louis. "The question is: What is it?…”