Mechanisms of oxidative stress resistance in the brain: Lessons learned from hypoxia tolerant extremophilic vertebrates

Abstract

The Oxidative Stress Theory of Aging has had tremendous impact in research involving aging and age-associated diseases including those that affect the nervous system. With over half a century of accrued data showing both strong support for and against this theory, there is a need to critically evaluate the data acquired from common biomedical research models, and to also diversify the species used in studies involving this proximate theory. One approach is to follow Orgel’s second axiom that “evolution is smarter than we are” and judiciously choose species that may have evolved to live with chronic or seasonal oxidative stressors. Vertebrates that have naturally evolved to live under extreme conditions (e.g., anoxia or hypoxia), as well as those that undergo daily or seasonal torpor encounter both decreased oxygen availability and subsequent reoxygenation, with concomitant increased oxidative stress. Due to its high metabolic activity, the brain may be particularly vulnerable to oxidative stress. Here, we focus on oxidative stress responses in the brains of certain mouse models as well as extremophilic vertebrates. Exploring the naturally evolved biological tools utilized to cope with seasonal or environmentally variable oxygen availability may yield key information pertinent for how to deal with oxidative stress and thereby mitigate its propagation of age-associated diseases.

Extended Postnatal Brain Development in the Longest-Lived Rodent: Prolonged Maintenance of Neotenous Traits in the Naked Mole-Rat Brain

“…Curiously, full-grown NMRs display many traits that are considered neotenous when compared to other rodents (Maina et al, 1992; Buffenstein, 2001). Some of these traits may be ecophysiological adaptations to life in underground, sealed, hypoxic, and hypercapnic burrows (Buffenstein, 1996; Kim et al, 2011; Fang et al, 2014; Garbarino et al, 2015), a niche inhabited since the early Miocene. Moreover, many of these traits are shared among the two African mole-rat families (Bathyergidae and Heterocephalidae) as well as the more distant Asian and Middle Eastern mole-rats (Faulkes et al, 2004; Upham and Patterson, 2012).…”

Seasonal and post-trauma remodeling in cone-dominant ground squirrel retina

“…Recent reviews address the GS’s intrinsic tolerance of brain hypoxia (Garbarino et al, 2015; Larson et al, 2014) and brain ischemia (Lee & Hallenbeck, 2013), supporting the notion that hibernation is a neuroprotected state (Dave et al, 2012). Moreover, presynaptic ribbon dynamics similar to that seen in cones have also been reported in GS pinealocytes (McNulty et al, 1990).…”

Naked mole-rat acid-sensing ion channel 3 forms nonfunctional homomers, but functional heteromers

“…Moreover, naked mole-rats show behavioral indifference to both ammonia and acid fumes (38,39), as well as CO 2 (40) at levels producing avoidance in mice. All of these findings demonstrate likely adaptations to having evolved in a subterranean, hypoxic/hypercapnic environment (45,46). Here we undertook to investigate the properties of nmrASIC3 because evidence supports a role for ASIC3 in a wide variety of situations, including: pain (9, 23-26), as well itch (29), mechanosensation (23,30) and anxiety (31).…”