Walking the Oxidative Stress Tightrope: A Perspective from the Naked Mole-Rat, the Longest-Living Rodent

Sam and Ann Barshop Institute for Aging and Longevity Studies, University of Texas Health Science Center at San Antonio, 15355 Lambda Dr. San Antonio, TX 78245, USA.
Current pharmaceutical design (Impact Factor: 3.45). 07/2011; 17(22):2290-307. DOI: 10.2174/138161211797052457
Source: PubMed


Reactive oxygen species (ROS), by-products of aerobic metabolism, cause oxidative damage to cells and tissue and not surprisingly many theories have arisen to link ROS-induced oxidative stress to aging and health. While studies clearly link ROS to a plethora of divergent diseases, their role in aging is still debatable. Genetic knock-down manipulations of antioxidants alter the levels of accrued oxidative damage, however, the resultant effect of increased oxidative stress on lifespan are equivocal. Similarly the impact of elevating antioxidant levels through transgenic manipulations yield inconsistent effects on longevity. Furthermore, comparative data from a wide range of endotherms with disparate longevity remain inconclusive. Many long-living species such as birds, bats and mole-rats exhibit high-levels of oxidative damage, evident already at young ages. Clearly, neither the amount of ROS per se nor the sensitivity in neutralizing ROS are as important as whether or not the accrued oxidative stress leads to oxidative-damage-linked age-associated diseases. In this review we examine the literature on ROS, its relation to disease and the lessons gleaned from a comparative approach based upon species with widely divergent responses. We specifically focus on the longest lived rodent, the naked mole-rat, which maintains good health and provides novel insights into the paradox of maintaining both an extended healthspan and lifespan despite high oxidative stress from a young age.

Download full-text


Available from: Karl Rodriguez, Oct 07, 2015
133 Reads
  • Source
    • "To further assess the role that autophagy may contribute to the sustained healthspan of the NMR by regulating cellular proteostasis, the PI3K/Akt/mTOR axis, Beclin-1 and LC3 were examined in the NMR brain as a function of age. Previous data suggested that the NMR, under basal conditions, maintains higher levels of autophagy, thereby removing potentially toxic proteins before they can negatively impact organ functionality [13] and that macroautophagy was shown to be substantially higher in NMRs than in shorter-lived mice [13] [16]. Further, when the autophagy markers LC3-I, LC3-II and Beclin-1 were measured in one-day-old NMRs and one-day-old mice, the NMRs were shown to have a higher LC3-II/LC3-I ratio, even though their Beclin-1 levels were lower, suggesting that NMRs have a significantly higher basal levels of autophagy than mice [7]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The naked mole-rat (NMR) is the longest-lived rodent and possesses several exceptional traits: marked cancer resistance, negligible senescence, prolonged genomic integrity, pronounced proteostasis, and a sustained health span. The underlying molecular mechanisms that contribute to these extraordinary attributes are currently under investigation to gain insights that may conceivably promote and extend human health span and lifespan. The ubiquitin-proteasome and autophagy-lysosomal systems play a vital role in eliminating cellular detritus to maintain proteostasis and have been previously shown to be more robust in NMRs when compared with shorter-lived rodents. Using a 2-D PAGE proteomics approach, differential expression and phosphorylation levels of proteins involved in proteostasis networks were evaluated in the brains of NMRs in an age-dependent manner. We identified 9 proteins with significantly altered levels and/or phosphorylation states that have key roles involved in proteostasis networks. To further investigate the possible role that autophagy may play in maintaining cellular proteostasis, we examined aspects of the PI3K/Akt/mammalian target of rapamycin (mTOR) axis as well as levels of Beclin-1, LC3-I, and LC3-II in the brain of the NMR as a function of age. Together, these results show that NMRs maintain high levels of autophagy throughout the majority of their lifespan and may contribute to the extraordinary health span of these rodents. The potential of augmenting human health span via activating the proteostasis network will require further studies. Copyright © 2015. Published by Elsevier B.V.
    Biochimica et Biophysica Acta 08/2015; 1852(10 Pt A). DOI:10.1016/j.bbadis.2015.08.002 · 4.66 Impact Factor
  • Source
    • "The mole-rat tissues are characterized by high levels of oxidative damage accompanied by exceptional protein stability and stress resistance [192]. Such paradox features were found in other long lived organisms such as certain birds or bats [193]. The analysis of liver extracts from naked mole-rats revealed a general upregulation of the proteasomes, as compared with age-matched mice: higher ChT-L and T-L activities, more active 20S cores, more populous and more active 26S complexes and, most strikingly, greater content of immunoproteasomes [118]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The giant proteolytic factory called the proteasome came a long way from a biochemical curio to a major regulator of cellular physiology and a renowned drug target within the ubiquitin proteasome pathway (UPP). Thanks to availability of highly specific inhibitors of the proteasome, in less than twenty years it was possible to identify major transcription factors, cyclins, and products of oncogenes as crucial substrates for the UPP. Nine years passed since the FDA speedily approved bortezomib, the inhibitor of proteasome for treatment of multiple myeloma. One year after its approval, the field was honored by awarding the Nobel Prize to Hershko, Ciechanover and Rose for introducing the concept of controlled proteolysis of ubiquitin-tagged substrates, with proteasome as the intracellular recycling facility. Taking into consideration the universal involvement of the proteasome in the life of all cells in human body, it comes to no surprise that the enzyme is deeply implicated in etiology, progression, diagnosis or cure of multiple diseases. Below we discuss some aspects of the implication: from direct causative links to changes in proteasome properties that correlate with pathological conditions. We start with diseases collectively known as cancer, and with immune system-related pathologies. Here, the proteasome inhibitors are either already used in clinics, or undergo advanced preclinical screening. Then, we will continue with cardiovascular disorders, followed by aging. Changes of the proteasome make-up during aging may be a priming factor for neurodegenerative diseases, described last. We discuss the potential for proteasome regulation: inhibition, activation or specificity modulation, to successfully enter the clinical setting.
    Current pharmaceutical design 09/2012; 19(6). DOI:10.2174/13816128130604 · 3.45 Impact Factor
  • Source
    • "Methionine restriction Undetermined Reduced Increased Sanz et al., 2006, Naudí et al. (2007), Perrone et al., 2010 a Limitation of total food intake (without vitamin and mineral supplementation). et al., 2007), albeit with notable exceptions (Rodriguez et al., 2011). Furthermore, aged animals accumulate oxidatively damaged biomolecules in their mitochondria, in a manner prevented by life-span enhancing interventions such as CR and methionine restriction (reviewed by Shigenaga et al., 1994; Balaban et al., 2005; Pamplona and Barja, 2006; Kowaltowski et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mitochondrial energy metabolism and mitochondrially-derived oxidants have, for many years, been recognized as central toward the effects of aging. A body of recent work has focused on the relationship between mitochondrial redox state, aging and dietary interventions that affect lifespan. These studies have uncovered mechanisms through which diet alters mitochondrial metabolism, in addition to determining how these changes affect oxidant generation, which in itself has an impact on mitochondrial function in aged animals. Many of the studies conducted to date, however, are correlative, and it remains to be determined which of the energy metabolism and redox modifications induced by diet are central toward lifespan extent. Furthermore, dietary interventions used for laboratory animals are often unequal, and of difficult comparison with humans (for whom, by nature, no long-term sound scientific information on the effects of diet on mitochondrial redox state and aging is available). We hope future studies will be able to mechanistically characterize which energy metabolism and redox changes promoted by dietary interventions have positive lifespan effects, and translate these findings into human prevention and treatment of age-related disease.
    Ageing research reviews 04/2012; 12(1):22-28. DOI:10.1016/j.arr.2012.03.009 · 4.94 Impact Factor
Show more