Aspects of the energetics and renal physiology of some African arid-adapted rodents

Bibliography: leaves 358-363.The following aspects of physiological adaptation and resource usage were examined in several species of arid-adapted African rodents: The effect of temperature on thermoregulation, metabolism, evaporative water loss and thermal conductance was studied in the North East African pigmy gerbil, gerbillus ppusillus; This gerbil did not strictly maintain homoeothermy and like most arid-adapted rodents had a reduced basal metabolic rate. When G. pusillus was maintained on an ad lib. food and water diet, its daily energy expenditure was similar to that predicted by mass. This increased to 116% of the expected allometric value when deprived of water. On a diet of air-dried millet seeds, increased kidney concentrating ability, reduced pulmocutaneous evaporation and a reduction in faecal water loss, were sufficient to impart virtual independence of exogenous water and the maintenance of a positive water balance. If food was restricted, G. pusillus utilized torpor to precisely balance energy expenditure with that available and so maintained a constant body mass. During torpor, assimilation efficiency was significantly reduced. The cost of maintaining coenothermia for the full duration of food processing would be prohibitive and it was estimated that it would have utilised approximately 50% of the daily energy available. The cost of employing torpor (0.5kJ.day-1) on the other hand was insignificant in comparison with the savings accrued by the use of torpor (32.25kJ. day -1). Parsimony of water loss with food restriction enabled the maintenance of a positive water balance during this period. The importance of micro-habitat in thermoregulation was investigated in Gerbillurus paeba, inhabiting the thermally stable confines of a plugged burrow, and in Aethomys namaquensis, a crevice dwelling rock rat. The rock rat, living in an environment characterized by large diet ranges, precisely controlled body temperature. It did this by compensating for its reduced basal metabolic rate, with a low rate of thermal conductance. Gerbillurus paeba tolerated a labile body temperature and used a high rate of thermal conductance to remove metabolic heat, for the high humidities it encountered in its milieu would impede the use of evaporative cooling. Daily energy expenditure of both Namib rodents. Was monitored when they were maintained on a low fibre food source (golden millet) and then when this was replaced with a high fibre food source (high-bulk bran). Aethomys namaquensis showed a DEE similar to that predicted by mass and this remained constant, irrespective of the food source or the presence or absence of water. The DEE of G. paeba was more variable. When water was freely available DEE was higher than that predicted by mass and was similar to that predicted for an insectivore of similar body mass. This might reflect its propensity towards an insectivorous diet. When water-stressed on a high fibre diet, DEE of G. paeba declined by half, suggesting that G. paeba employed torpor when conditions were stressful and when the quality of resources was reduced. On a low fibre diet, both species were able to maintain a positive water balance when deprived of water, showing similar reductions in water loss to that of G. pusillus. Low assimilation efficiency and the concomitant increase in faecal water loss precluded the maintenance of a positive water balance when they were fed a high fibre food source. Despite increased urine concentrations and reduced evaporative water loss both species succumbed to chronic water-deprivation. Daily water turnovers and urine concentrating ability was monitored in 17 species of African rodents from arid areas. In general, rodents belonging to the Cricetidae exhibited lower water turnovers and voided smaller volumes of urine at significantly greater concentrations than the murids. All these cricetid rodents were found to produce a crystalline precipitate of allantoin in their urine when water stressed. The quantities of crystalline allantoin excreted were far greater than that expected from purine catabolism and accounted for 30% of the total nitrogenous wastes of the cricetids when deprived of water. It was thought that the substantial quantities of allantoin excreted were responsible for the lower water turnover rates in the cricetids. It is suggested, therefore, when water is limiting, there is a shift in the nitrogen pathway from urea to allantoin, so conferring an eco-physiological advantage to these long term residents of the arid regions of Africa

DNA methylation clocks as a predictor for ageing and age estimation in naked mole-rats, Heterocephalus glaber.

The naked mole-rat, Heterocephalus glaber (NMR), the longest-lived rodent, is of significance and interest in the study of biomarkers for ageing. Recent breakthroughs in this field have revealed 'epigenetic clocks' that are based on the temporal accumulation of DNA methylation at specific genomic sites. Here, we validate the hypothesis of an epigenetic clock in NMRs based on changes in methylation of targeted CpG sites. We initially analysed 51 CpGs in NMR livers spanning an age range of 39-1,144 weeks and found 23 to be significantly associated with age (p<0.05). We then built a predictor of age using these sites. To test the accuracy of this model, we analysed an additional set of liver samples, and were successfully able to predict their age with a root mean squared error of 166 weeks. We also profiled skin samples with the same age range, finding a striking correlation between their predicted age versus their actual age (R=0.93), but which was lower when compared to the liver, suggesting that skin ages slower than the liver in NMRs. Our model will enable the prediction of age in wild-caught and captive NMRs of unknown age, and will be invaluable for further mechanistic studies of mammalian ageing

Naked mole-rats maintain healthy skeletal muscle and Complex IV mitochondrial enzyme function into old age

This project was funded by Newcastle University Centre for Brain Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council and Medical Research Council [G0700718]), the UK NIHR Biomedical Research Centre in Age and Age Related Diseases award to the Newcastle upon Tyne Hospitals NHS Foundation Trust, MRC Centre for Neuromuscular Disease [G000608-1], The Wellcome Trust Centre for Mitochondrial Research [096919/Z/11/Z]

Seasonal and daily variation in blood and urine concentrations of free-ranging Angolan free-tailed bats (Mops condylurus) in hot roosts in southern Africa

Urine and plasma concentrations and haematocrits were measured in free-ranging Angolan free-tailed bats (Mops condylurus) inhabiting thermally-challenging roosts in the Komatipoort region of South Africa. Samples were collected in both autumn and summer, from bats caught emerging from roosts before feeding (pre-feed- ing), and those returning after foraging (post-prandial). Post-prandial bats exhibited higher body fluid concentrations, but lower haematocrits, than individuals caught prior to feeding, reflecting raised excretory mineral and nitrogenous loads and replenishment of body water pools during nocturnal foraging. Pre-feeding concentrations of both urine (2637 ± 506 mOsm/kg; n = 16) and plasma (331.5 ± 25.9mOsm/kg; n = 24) were significantly higher in summer than autumn (urine: 2157 ± 454mOsm/kg; n = 8; plasma: 294.5 ± 35.2 mOsm/kg; n = 18) reflecting the greater dehydration stresses within hotter roost microclimates, and a moderate kidney concentrating ability in this species. Haematocrits of pre-feeding animals were not, however, influenced by season and in both instances exceeded 53%, indicative of the higher oxygen carrying capacity needed for sustained flight in volant insectivores and also the defense of the rheologica! properties of blood. The ability of Mops condylurus to withstand a thermally-challenging roost milieu reflects, in part, its tolerance to dehydration, rather than the maintenance of water balance through exceptional renal concentrating ability

Survival tactics within thermally-challenging roosts: heat tolerance and cold sensitivity in the Angolan free-tailed bat, Mops condylurus

We studied roost microclimates, thermal preferences and temperature-related variation in body temperatures and flight abilities of M. condylurus from three roosts in man-made structures in South Africa. Roosts were characterized by marked spatio-temporal variability in ambient temperature and relative humidity on a daily and seasonal basis. Microclimates were thermally challenging, being very hot (&gt;40°C) for several hours daily in summer and autumn, and cold (&lt;10°C) for much of the night in winter Thermal preference tests revealed that the bats actively selected temperature zones (35°- 42°C) in which basal metabolic rate could be maintained, and above the minimum necessary for sustained flight. This presumably allowed them to minimize energy costs of thermoregulation without compromising reproductive activity or their ability to avoid predators. Bats displayed pronounced heat tolerance and hyperthermia in response to prolonged experimental exposure to high temperatures (40°C). They also exhibited cold-sensitivity, characterized by hypothermia and entry into torpor, when exposed to ambient temperatures below the thermal neutral zone. This response to low ambient temperatures would conserve energy in cold periods when the high energetic costs of foraging may not be met owing to reduced insect availability. We hypothesize that this broad roosting tolerance has energetic, ecological and evolutionary benefits that outweigh attendant disadvantages, which are largely compensated for by an unusual physiology

Negligible senescence in naked mole rats may be a consequence of well-maintained splicing regulation

This is the final version. Available on open access from Springer Nature via the DOI in this recordNaked mole-rats (NMRs) have amongst the longest lifespans relative to body size of any known, non-volant mammalian species. They also display an enhanced stress resistance phenotype, negligible senescence and very rarely are they burdened with chronic age-related diseases. Alternative splicing (AS) dysregulation is emerging as a potential driver of senescence and ageing. We hypothesised that the expression of splicing factors, important regulators of patterns of AS, may differ in NMRs when compared to other species with relatively shorter lifespans. We designed assays specific to NMR splicing regulatory factors and also to a panel of pre-selected brain-expressed genes known to demonstrate senescence-related alterations in AS in other species, and measured age-related changes in the transcript expression levels of these using embryonic and neonatal developmental stages through to extreme old age in NMR brain samples. We also compared splicing factor expression in both young mouse and NMR spleen and brain samples. Both NMR tissues showed approximately double the expression levels observed in tissues from similarly sized mice. Furthermore, contrary to observations in other species, following a brief period of labile expression in early life stages, adult NMR splicing factors and patterns of AS for functionally relevant brain genes remained remarkably stable for at least two decades. These findings are consistent with a model whereby the conservation of splicing regulation and stable patterns of AS may contribute to better molecular stress responses and the avoidance of senescence in NMRs, contributing to their exceptional lifespan and prolonged healthspan.Calico Life Sciences LL

Catastrophic senescence and semelparity in the Penna aging model

The catastrophic senescence of the Pacific salmon is among the initial tests used to validate the Penna aging model. Based on the mutation accumulation theory, the sudden decrease in fitness following reproduction may be solely attributed to the semelparity of the species. In this work, we report other consequences of mutation accumulation. Contrary to earlier findings, such dramatic manifestation of aging depends not only on the choice of breeding strategy but also on the value of the reproduction age, R, and the mutation threshold, T. Senescence is catastrophic when $T \leq R$. As the organism's tolerance for harmful genetic mutations increases, the aging process becomes more gradual. We observe senescence that is threshold dependent whenever T>R. That is, the sudden drop in survival rate occurs at age equal to the mutation threshold value

RNA Sequencing Reveals Differential Expression of Mitochondrial and Oxidation Reduction Genes in the Long-Lived Naked Mole-Rat When Compared to Mice

The naked mole-rat (Heterocephalus glaber) is a long-lived, cancer resistant rodent and there is a great interest in identifying the adaptations responsible for these and other of its unique traits. We employed RNA sequencing to compare liver gene expression profiles between naked mole-rats and wild-derived mice. Our results indicate that genes associated with oxidoreduction and mitochondria were expressed at higher relative levels in naked mole-rats. The largest effect is nearly 300-fold higher expression of epithelial cell adhesion molecule (Epcam), a tumour-associated protein. Also of interest are the protease inhibitor, alpha2-macroglobulin (A2m), and the mitochondrial complex II subunit Sdhc, both ageing-related genes found strongly over-expressed in the naked mole-rat. These results hint at possible candidates for specifying species differences in ageing and cancer, and in particular suggest complex alterations in mitochondrial and oxidation reduction pathways in the naked mole-rat. Our differential gene expression analysis obviated the need for a reference naked mole-rat genome by employing a combination of Illumina/Solexa and 454 platforms for transcriptome sequencing and assembling transcriptome contigs of the non-sequenced species. Overall, our work provides new research foci and methods for studying the naked mole-rat's fascinating characteristics

Blunted Neuronal Calcium Response to Hypoxia in Naked Mole-Rat Hippocampus

Naked mole-rats are highly social and strictly subterranean rodents that live in large communal colonies in sealed and chronically oxygen-depleted burrows. Brain slices from naked mole-rats show extreme tolerance to hypoxia compared to slices from other mammals, as indicated by maintenance of synaptic transmission under more hypoxic conditions and three fold longer latency to anoxic depolarization. A key factor in determining whether or not the cellular response to hypoxia is reversible or leads to cell death may be the elevation of intracellular calcium concentration. In the present study, we used fluorescent imaging techniques to measure relative intracellular calcium changes in CA1 pyramidal cells of hippocampal slices during hypoxia. We found that calcium accumulation during hypoxia was significantly and substantially attenuated in slices from naked mole-rats compared to slices from laboratory mice. This was the case for both neonatal (postnatal day 6) and older (postnatal day 20) age groups. Furthermore, while both species demonstrated more calcium accumulation at older ages, the older naked mole-rats showed a smaller calcium accumulation response than even the younger mice. A blunted intracellular calcium response to hypoxia may contribute to the extreme hypoxia tolerance of naked mole-rat neurons. The results are discussed in terms of a general hypothesis that a very prolonged or arrested developmental process may allow adult naked mole-rat brain to retain the hypoxia tolerance normally only seen in neonatal mammals