Metabolic and Microbial Mastery: Unveiling the Secrets of Naked Mole-Rat Longevity

TL;DR

Naked mole-rats live exceptionally long lives due to unique metabolic and microbial traits that protect against aging and disease.

Contribution

The study reveals novel metabolic and microbiome adaptations in naked mole-rats that contribute to their extraordinary longevity.

Findings

Naked mole-rats switch to fructose metabolism and maintain high glycogen and glutathione levels for energy and stress resistance.

They have distinct metabolomic profiles with lower methionine pathway amino acids and elevated anti-aging metabolites.

Their gut microbiome remains stable with age, except for increased Methanomassiliicoccus intestinalis in older individuals.

Abstract

Naked mole-rats (Heterocephalus glaber) stand out among mammals for their extraordinary longevity, showing no increase in mortality risk with age and maintaining robust physiological and molecular stability throughout their 40-year lifespan. These subterranean herbivorous rodents have evolved remarkable adaptations for thriving in low-oxygen environments, including the ability to switch from glucose to fructose metabolism, supporting sustained anaerobic activity. Elevated glycogen stores provide a vital energy reserve for anaerobic ATP production, while increased glutathione levels offer a strong defense against oxidative stress, contributing to their exceptional health span and cancer resistance. Metabolomic analyses reveal significant distinctions between naked mole-rats and laboratory mice, notably in their lower plasma levels of methionine pathway amino acids, akin to longevity-associated states such as calorie restriction. Additionally, they exhibit enriched lipid sub-pathways related to membrane composition and sterols, enhancing biological resilience. Elevated concentrations of anti-aging metabolites like α-tocopherol and N8-acetylspermidine further underscore their unique metabolic profile. Unlike mice, naked mole-rats’ gut microbiome remains stable with age, showing minimal changes in microbial populations, suggesting a robust microbiome beneficial for sustained good health. The one exception is the Archaea, Methanomassiliicoccus intestinalis, which is absent in the mouse microbiome, and increases in abundance in aging mole-rats. This comprehensive metabolomic and microbiome signature reflects evolutionary adaptations surpassing typical age-related changes, offering valuable insights into their longevity and disease resistance, with potential implications for human health interventions.