Nigel C. Bennett

) social and subterranean lifestyle generates a hypoxic niche. Under experimental conditions, naked mole-rats tolerate hours of extreme hypoxia and survive 18 minutes of total oxygen deprivation (anoxia) without apparent injury. During anoxia, the naked mole-rat switches to anaerobic metabolism fueled by fructose, which is actively accumulated and metabolized to lactate in the brain. Global expression of the GLUT5 fructose transporter and high levels of ketohexokinase were identified as molecular signatures of fructose metabolism. Fructose-driven glycolytic respiration in naked mole-rat tissues avoids feedback inhibition of glycolysis via phosphofructokinase, supporting viability. The metabolic rewiring of glycolysis can circumvent the normally lethal effects of oxygen deprivation, a mechanism that could be harnessed to minimize hypoxic damage in human disease.

Chronic kidney disease (CKD) is a common and serious problem that adversely affects human health, limits longevity and increases costs to health-care systems worldwide. Its increasing incidence cannot be fully explained by traditional risk factors. Oxidative stress is prevalent in CKD patients and is considered to be an important pathogenic mechanism. Oxidative stress develops from an imbalance between free radical production often increased through dysfunctional mitochondria formed with increasing age, type 2 diabetes mellitus, inflammation, and reduced anti-oxidant defences. Perturbations in cellular oxidant handling influence downstream cellular signalling and, in the kidney, promote renal cell apoptosis and senescence, decreased regenerative ability of cells, and fibrosis. These factors have a stochastic deleterious effect on kidney function. The majority of studies investigating anti-oxidant treatments in CKD patients show a reduction in oxidative stress and many show improved renal function. Despite heterogeneity in the oxidative stress levels in the CKD population, there has been little effort to measure patient oxidative stress levels before the use of any anti-oxidants therapies to optimize outcome. This review describes the development of oxidative stress, how it can be measured, the involvement of mitochondrial dysfunction and the molecular pathways that are altered, the role of oxidative stress in CKD pathogenesis and an update on the amelioration of CKD using anti-oxidant therapies.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

In many animal societies, dominant individuals monopolize reproduction, but the tactics they employ to achieve this are poorly understood. One possibility is that aggressive dominants render their subordinates infertile by inducing chronic physiological "stress." However, this hypothesis has been discarded largely for cooperatively breeding species, where reproductive monopolies are often extreme. Here we provide strong support for the stress-related suppression hypothesis in a cooperative mammal, the meerkat (Suricata suricatta). When pregnant, dominant females subject some subordinate females to escalating aggression, culminating in temporary evictions from the group. While evicted, subordinate females suffer chronic elevation of their glucocorticoid adrenal hormone levels, reproductive down-regulation (reduced pituitary sensitivity to gonadotropin-releasing hormone), reduced conception rates, and increased abortion rates. Rather than constantly harassing all subordinate females, dominants only become aggressive when pregnant themselves (when subordinate reproduction would otherwise conflict with their own) and target those females with whom reproductive conflict is most likely (older, pregnant, and more distantly related females). Our findings suggest that dominant female meerkats employ stressful evictions to suppress reproduction among their probable competitors, when attempting to breed themselves. Given the lack of evidence for stress-related suppression in other cooperative breeders to date, it is clear that social stress alone cannot account for the reproductive failure of subordinates across such societies. However, our findings raise the possibility that, in some cooperative breeders at least, dominants may employ stress-related suppression as a backup mechanism to guard against lapses in reproductive restraint by their subordinates.