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Published on: December 1, 2023
The exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses
Daniel Munro1,2,3, Cécile Baldy2, Matthew E Pamenter2,4
1Department of Biological Sciences, University of Manitoba, Winnipeg, Manitoba, Canada.
Abstract:
Naked mole-rats (NMRs) are mouse-sized mammals that exhibit an exceptionally long lifespan (>30 vs. <4 years for mice), and resist aging-related pathologies such as cardiovascular and pulmonary diseases, cancer, and neurodegeneration. However, the mechanisms underlying this exceptional longevity and disease resistance remain poorly understood. The oxidative stress theory of aging posits that (a) senescence results from the accumulation of oxidative damage inflicted by reactive oxygen species (ROS) of mitochondrial origin, and (b) mitochondria of long-lived species produce less ROS than do mitochondria of short-lived species. However, comparative studies over the past 28 years have produced equivocal results supporting this latter prediction. We hypothesized that, rather than differences in ROS generation, the capacity of mitochondria to consume ROS might distinguish long-lived species from short-lived species. To test this hypothesis, we compared mitochondrial production and consumption of hydrogen peroxide (H2 O2 ; as a proxy of overall ROS metabolism) between NMR and mouse skeletal muscle and heart. We found that the two species had comparable rates of mitochondrial H2 O2 generation in both tissues; however, the capacity of mitochondria to consume ROS was markedly greater in NMRs. Specifically, maximal observed consumption rates were approximately two and fivefold greater in NMRs than in mice, for skeletal muscle and heart, respectively. Our results indicate that differences in matrix ROS detoxification capacity between species may contribute to their divergence in lifespan.
Insights
Naked mole-rats live exceptionally long lives, resisting aging. Unlike mice, their mitochondria better detoxify reactive oxygen species (ROS), suggesting enhanced ROS consumption, not reduced production, contributes to longevity.
Area of Science:
- Comparative biology
- Gerontology
- Mitochondrial biology
Background:
- Naked mole-rats (NMRs) display remarkable longevity and resistance to age-related diseases, unlike short-lived mice.
- The oxidative stress theory of aging suggests reduced mitochondrial reactive oxygen species (ROS) production in long-lived species, but evidence is equivocal.
Purpose of the Study:
- To investigate whether enhanced mitochondrial ROS consumption, rather than reduced ROS generation, differentiates long-lived naked mole-rats from short-lived mice.
- To compare mitochondrial hydrogen peroxide (H2O2) production and consumption between NMR and mouse skeletal muscle and heart tissues.
Main Methods:
- Comparative analysis of mitochondrial hydrogen peroxide (H2O2) generation and consumption rates.
- Utilized skeletal muscle and heart tissues from naked mole-rats and mice.
- Measured H2O2 production and maximal consumption capacity in isolated mitochondria.
Main Results:
- Mitochondria from naked mole-rats and mice exhibited comparable rates of H2O2 generation.
- Mitochondrial ROS consumption capacity was significantly higher in naked mole-rats compared to mice.
- Maximal H2O2 consumption rates were ~2-fold greater in NMR skeletal muscle and ~5-fold greater in NMR heart tissue.
Conclusions:
- Enhanced mitochondrial ROS detoxification capacity, specifically increased ROS consumption, may be a key factor contributing to the exceptional longevity and disease resistance of naked mole-rats.
- Findings challenge the traditional oxidative stress theory's focus on ROS production and highlight the importance of ROS scavenging mechanisms in aging.
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