Lipidome determinants of maximal lifespan in mammals

Maximal lifespan of mammalian species, even if closely related, may differ more than 10-fold, however the nature of the mechanisms that determine this variability is unresolved. Here, we assess the relationship between maximal lifespan duration and concentrations of more than 20,000 lipid compounds, measured in 669 tissue samples from 6 tissues of 35 species representing three mammalian clades: primates, rodents and bats. We identify lipids associated with species’ longevity across the three clades, uncoupled from other parameters, such as basal metabolic rate, body size, or body temperature. These lipids clustered in specific lipid classes and pathways, and enzymes linked to them display signatures of greater stabilizing selection in long-living species, and cluster in functional groups related to signaling and protein-modification processes. These findings point towards the existence of defined molecular mechanisms underlying variation in maximal lifespan among mammals.The National Natural Science Foundation of China (grant 31420103920), Strategic Priority Research Program of the Chinese Academy of Sciences (grant XDB13010200), the National Natural Science Foundation of China (grant 91331203), the National One Thousand Foreign Experts Plan (grant WQ20123100078), the Bureau of International Cooperation, Chinese Academy of Sciences (grant GJHZ201313) and the Federal Targeted Program for Research and Development in Priority Areas of Advancement of the Russian Scientific and Technological Complex for 2014–2020 (the Ministry of Education and Science of the Russian Federation), grant № 14.615.21.0002, the Unique identifier of the agreement: RFMEFI61515×0002. Additional support was obtained from the European Research Council (advanced grant 294678 to GRL).http://www.nature.com/scientificreportsam2017Zoology and Entomolog

The naked truth:a comprehensive clarification and classification of current 'myths' in naked mole-rat biology

The naked mole-rat (Heterocephalus glaber) has fascinated zoologists for at least half a century. It has also generated considerable biomedical interest not only because of its extraordinary longevity, but also because of unusual protective features (e.g. its tolerance of variable oxygen availability), which may be pertinent to several human disease states, including ischemia/reperfusion injury and neurodegeneration. A recent article entitled 'Surprisingly long survival of premature conclusions about naked mole-rat biology' described 28 'myths' which, those authors claimed, are a 'perpetuation of beautiful, but falsified, hypotheses' and impede our understanding of this enigmatic mammal. Here, we re-examine each of these 'myths' based on evidence published in the scientific literature. Following Braude et al., we argue that these 'myths' fall into four main categories: (i) 'myths' that would be better described as oversimplifications, some of which persist solely in the popular press; (ii) 'myths' that are based on incomplete understanding, where more evidence is clearly needed; (iii) 'myths' where the accumulation of evidence over the years has led to a revision in interpretation, but where there is no significant disagreement among scientists currently working in the field; (iv) 'myths' where there is a genuine difference in opinion among active researchers, based on alternative interpretations of the available evidence. The term 'myth' is particularly inappropriate when applied to competing, evidence-based hypotheses, which form part of the normal evolution of scientific knowledge. Here, we provide a comprehensive critical review of naked mole-rat biology and attempt to clarify some of these misconceptions

Lutzomyia Sand Fly Diversity and Rates of Infection by Wolbachia and an Exotic Leishmania Species on Barro Colorado Island, Panama

Certain sand fly species living inside or on the edge of tropical forests are well known to transmit a protozoan to humans, which in lowland Panama develops into a cutaneous form of leishmaniasis; open, itching sores on the face and extremities requiring aggressive treatment with antimonial compounds. Morphological characters and DNA sequence from mitochondrial and nuclear gene fragments permitted us to identify and then establish historical relationships among 20 common sand fly species occurring in the understory of Barro Colorado Island, a forested preserve in the middle of the Panama Canal. Individuals in three of these sand fly species were found to be 26–43% infected by Leishmania naiffi, a species hitherto known only from the Amazonian region and the Caribbean. We then screened the same 20 sand fly species for the cytoplasmically transmitted bacteria Wolbachia pipientis, finding three infected at high rates, each by a distinct strain. Lutzomyia trapidoi, the most likely transmitter of Leishmania to humans in Panama, was among the Wolbachia-infected species, thus marking it as a possible high-value target for future biocontrol studies using the bacteria either to induce mating incompatabilities or to drive selected genes into the population

Comparative biology of longevity: the molecular mechanisms promoting long lifespan in the naked mole-rat (Heterocephalus glaber)

Thesis (Ph. D.)--University of Rochester. Dept. of Biology, 2013.This thesis addresses the proximal molecular mechanisms responsible for the longevity of the naked mole-rat (Heterocephalus glaber, hereafter NMR) compared to the short-lived laboratory mouse. One major contributor to short lifespan in the mouse is susceptibility to oncogenesis relative to other mammals. In contrast, the NMR is highly resistant to neoplasia. I describe work done in collaboration with Dr. Christopher Hine and Xiao Tian showing that high molecular weight hyaluronan is an important anti-tumor defense in the NMR. We use both in vitro and in vivo approaches to show that hyaluronan loss is necessary for transformation of NMR fibroblasts. Additionally, I characterized the NMR INK4a/b tumor suppressor locus. Normally, INK4a/b produces three tumor-suppressor proteins: p16INK4a, p15INK4b, and ARF. I show that the NMR additionally produces a splice variant that joins E1 from INK4b to E2 from INK4a. I confirmed expression of this variant in tissue culture and in vivo. I demonstrate that it is upregulated by hyaluronan and downregulated after hyaluronidase treatment. Overexpression of the variant confirmed it had biological activity similar to p16INK4a, which may contribute to NMR tumor resistance and longevity. NMR cells are exceptionally slow-growing compared to other rodent cell lines, even in optimal (physiological) tissue culture conditions. We detected an unusual ribosomal break in the NMR, and this led us to assay ribosomal translation rate. I constructed translational fidelity reporter plasmids, which were used to assay the accuracy of the NMR ribosome. We found that NMR cells had a similar overall translation rate as mouse cells, but their translational fidelity was four-fold higher. We propose that higher translational fidelity contributes to the lifespan of the NMR. Lastly, I compared the expression of IGF1R protein (a conserved regulator of lifespan from worms to humans) in a variety of tissues from all rodents available in our lab. I identified a strong inverse correlation between the level of expression of IGF1R in the brain tissue of rodents and their maximum lifespan. This correlation was maintained after phylogenetic correction using independent contrasts. This supports the idea that neuroendocrine signaling contributes to maximum lifespan of long-lived rodents

Integration of fluorescence in situ hybridization and chromosome-length genome assemblies revealed synteny map for guinea pig, naked mole-rat, and human.

Descriptions of karyotypes of many animal species are currently available. In addition, there has been a significant increase in the number of sequenced genomes and an ever-improving quality of genome assembly. To close the gap between genomic and cytogenetic data we applied fluorescent in situ hybridization (FISH) and Hi-C technology to make the first full chromosome-level genome comparison of the guinea pig (Cavia porcellus), naked mole-rat (Heterocephalus glaber), and human. Comparative chromosome maps obtained by FISH with chromosome-specific probes link genomic scaffolds to individual chromosomes and orient them relative to centromeres and heterochromatic blocks. Hi-C assembly made it possible to close all gaps on the comparative maps and to reveal additional rearrangements that distinguish the karyotypes of the three species. As a result, we integrated the bioinformatic and cytogenetic data and adjusted the previous comparative maps and genome assemblies of the guinea pig, naked mole-rat, and human. Syntenic associations in the two hystricomorphs indicate features of their putative ancestral karyotype. We postulate that the two approaches applied in this study complement one another and provide complete information about the organization of these genomes at the chromosome level

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Genome-wide adaptive complexes to underground stresses in blind mole rats Spalax

The blind mole rat (BMR), Spalax galili, is an excellent model for studying mammalian adaptation to life underground and medical applications. The BMR spends its entire life underground, protecting itself from predators and climatic fluctuations while challenging it with multiple stressors such as darkness, hypoxia, hypercapnia, energetics and high pathonecity. Here we sequence and analyse the BMR genome and transcriptome, highlighting the possible genomic adaptive responses to the underground stressors. Our results show high rates of RNA/DNA editing, reduced chromosome rearrangements, an over-representation of short interspersed elements (SINEs) probably linked to hypoxia tolerance, degeneration of vision and progression of photoperiodic perception, tolerance to hypercapnia and hypoxia and resistance to cancer. The remarkable traits of the BMR, together with its genomic and transcriptomic information, enhance our understanding of adaptation to extreme environments and will enable the utilization of BMR models for biomedical research in the fight against cancer, stroke and cardiovascular diseases