Biology subjects

Gladyshev, V. N.

Publications and source records attributed to Gladyshev, V. N..

81 records · Page 5Linked to original sources

bioRxiv2020

The landscape of longevity across phylogeny

Lifespan of model organisms can be extended by genetic, dietary and pharmacological interventions, but these effects may be negated by other factors. To understand robustness of longevity interventions within and across species, we analyzed age-dependent mortality of yeast, fruit flies, nematodes and mice subjected to thousands of genetic, pharmacological or dietary interventions, and applied the principles learned to other organisms. Across phylogeny, the accessible space of lifespan distribution functions, the "landscape of longevity", has a distinct structure of a fiber bundle, with individual fibers given by Strehler-Mildvan degeneracy manifolds. Within species, most interventions perturb parameters of survival curves along particular degeneracy manifolds. Transitions across manifolds are difficult to achieve, but they may lead to robust lifespan-modulating effects. Analyses of intraspecific degeneracy manifolds revealed soft bounds on achievable longevity. For humans, this bound is [~]138 years.

systems biology↗

bioRxiv2020

Multi-faceted deregulation of gene expression and protein synthesis with age

Protein synthesis represents a major metabolic activity of the cell. However, how it is affected by aging and how this in turn impacts cell function remains largely unexplored. To address this question, herein we characterized age-related changes in both the transcriptome and translatome of mouse tissues over the entire lifespan. Expression of the majority of differentially expressed genes followed a U-shaped curve with the turning point around 3-months-old. We showed that transcriptome changes govern changes in the translatome and are associated with altered expression of genes involved in inflammation, extracellular matrix and lipid metabolism. We also identified genes that may serve as candidate biomarkers of aging. At the translational level, we uncovered sustained down-regulation of a set of 5 terminal oligopyrimidine (5TOP) transcripts encoding protein synthesis and ribosome biogenesis machinery and regulated by the mTOR pathway. For many of them, ribosome occupancy dropped 3-fold or even more. Moreover, with age, ribosome coverage gradually decreased in the vicinity of start codons and increased near stop codons, revealing complex age-related changes in the translation process. Taken together, our results reveal systematic and multi-dimensional deregulation in protein synthesis, showing how this major cellular process declines with age.

systems biology↗

bioRxiv2019

The hematopoietic landscape at single-cell resolution reveals unexpected stem cell features in naked mole-rats

Naked mole-rats are the longest-lived rodents endowed with resistance to cancer and age-related diseases, yet their stem cell characteristics remain enigmatic. We profiled the naked mole-rat hematopoietic system down to single-cell resolution, and identified several unique features likely contributing to longevity. In adult naked mole-rats red blood cells are formed in spleen and marrow, a neotenic feature beneficial for hypoxic environments and to prevent anemia. Platelet numbers are lower compared to short-lived mice, which may preclude age-related platelet increase and thrombosis. T cells mature in thymus and lymph nodes, providing a supply of T cells after age-related thymus involution. The pool of quiescent stem cells is higher than in mice, and HSCs overexpress an oxidative phosphorylation signature, revealing a new paradigm of stem cell metabolism to benefit longevity and oppose oncogenesis. Our work provides a platform to study immunology and stem cell biology in an animal model of healthy aging. HIGHLIGHTSO_LIFlow cytometry labelling panel to purify viable naked mole-rat HSPCs C_LIO_LIThe spleen as the major site of erythropoiesis in the naked mole-rat C_LIO_LINaked mole-rats show extrathymic T-cell development under homeostatic conditions C_LIO_LINaked mole-rat hematopoietic stem cells (HSCs) have high OXPHOS activity C_LI

immunology↗

bioRxiv2019

Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals

All living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. As budding yeast cells age, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. Here we show that the transient induction of genomic instability, in the form of a low number of non-mutagenic DNA breaks, accelerates many of the chromatin and tissue changes seen during aging, including the erosion of the epigenetic landscape, a loss of cellular identity, advancement of the DNA methylation clock and cellular senescence. These data support a model in which a loss of epigenetic information is a cause of aging in mammals.\n\nOne Sentence SummaryThe act of repairing DNA breaks induces chromatin reorganization and a loss of cell identity that may contribute to mammalian aging

molecular biology↗

bioRxiv2019

Germline burden of rare damaging variants negatively affects human healthspan and lifespan

Genome-wide association studies often explore links between particular genes and phenotypes of interest. Known genetic variants, however, are responsible for only a small fraction of human lifespan variation evident from genetic twin studies. To account for the missing longevity variance, we hypothesized that the cumulative effect of deleterious variants may affect human longevity. Here, we report that the burden of rarest protein-truncating variants (PTVs) negatively impacts both human healthspan and lifespan in two large independent cohorts. Longer-living subjects have both fewer rarest PTVs and less damaging PTVs. In contrast, we show that the burden of frequent PTVs and rare non-PTVs is less deleterious, lacking association with longevity. The combined effect of rare PTVs is similar to that of known variants associated with longer lifespan and accounts for 1 - 2 years of lifespan variability. We further find that somatic accumulation of PTVs accounts for a minute fraction of mortality and morbidity acceleration and hence provides little support for its causal role in aging. Thus, damaging mutations, germline and somatic, can only contribute to aging as a result of higher-order effects including interactions of multiple forms of damage.

genetics↗

bioRxiv2019

Reversal of ageing- and injury-induced vision loss by Tet-dependent epigenetic reprogramming

Ageing is a degenerative process leading to tissue dysfunction and death. A proposed cause of ageing is the accumulation of epigenetic noise, which disrupts youthful gene expression patterns that are required for cells to function optimally and recover from damage1-3. Changes to DNA methylation patterns over time form the basis of an ageing clock4, 5, but whether old individuals retain information to reset the clock and, if so, whether this would improve tissue function is not known. Of all the tissues in the body, the central nervous system (CNS) is one of the first to lose regenerative capacity6, 7. Using the eye as a model tissue, we show that expression of Oct4, Sox2, and Klf4 genes (OSK) in mice resets youthful gene expression patterns and the DNA methylation age of retinal ganglion cells, promotes axon regeneration after optic nerve crush injury, and restores vision in a mouse model of glaucoma and in normal old mice. This process, which we call recovery of information via epigenetic reprogramming or REVIVER, requires the DNA demethylases Tet1 and Tet2, indicating that DNA methylation patterns dont just indicate age, they participate in ageing. Thus, old tissues retain a faithful record of youthful epigenetic information that can be accessed for functional age reversal.

molecular biology↗

bioRxiv2018

Human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects

Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/507780_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@1ad6feaorg.highwire.dtl.DTLVardef@18e72a9org.highwire.dtl.DTLVardef@109f18aorg.highwire.dtl.DTLVardef@1d0c9b7_HPS_FORMAT_FIGEXP M_FIG C_FIG AbstractThe human gut microbiome is a complex ecosystem that both affects and is affected by its host status. Previous analyses of gut microflora revealed associations between specific microbes and host health and disease status, genotype and diet. Here, we developed a method of predicting biological age of the host based on the microbiological profiles of gut microbiota using a curated dataset of 1,165 healthy individuals (3,663 microbiome samples). Our predictive model, a human microbiome clock, has an architecture of a deep neural network and achieves the accuracy of 3.94 years mean absolute error in cross-validation. The performance of the deep microbiome clock was also evaluated on several additional populations. We further introduce a platform for biological interpretation of individual microbial features used in age models, which relies on permutation feature importance and accumulated local effects. This approach has allowed us to define two lists of 95 intestinal biomarkers of human aging. We further show that this list can be reduced to 39 taxa that convey the most information on their hosts aging. Overall, we show that (a) microbiological profiles can be used to predict human age; and (b) microbial features selected by models are age-related.

bioinformatics↗

bioRxiv2018

Use of selenocysteine, the 21st amino acid, in the fungal kingdom

Selenoproteins are a diverse class of proteins containing selenocysteine (Sec), the 21st amino acid, incorporated into proteins during translation through a unique recoding mechanism. Selenoproteins fulfil essential roles in several lineages, including vertebrates; yet, they are not ubiquitous across the tree of life. In particular, the fungal kingdom was thought to lack selenoproteins, a paradigm that we defy here. We show that the genetic machinery for Sec utilization is present in the genomes of five species belonging to diverse early-branching fungal phyla (Chytridiomycota, Zoopagomycota, and Mucoromycota). We identified several selenoprotein genes in each of these genomes, and we detected canonical Sec insertion RNA structures (SECIS elements) for some of them. The identified selenoproteins are known or predicted oxidoreductases, some of which are conserved in mammals. Phylogenetic analyses support a scenario of vertical inheritance of the Sec trait within eukaryotes and fungi. Sec was then lost in numerous independent events in various fungal lineages, even within Sec-containing phyla. Notably, Sec was lost at the base of Dikarya, resulting in the absence of this trait in Saccharomyces cerevisiae and other well studied fungi. Our results indicate that, despite scattered occurrence, selenoproteins are found in all kingdoms of life.

genomics↗

bioRxiv2018

Organ-specific translation elongation rates measured by in vivo ribosome profiling

Protein synthesis and degradation are intricate biological processes involving more than a hundred proteins operating in a highly orches-trated fashion. Despite the progress, few options are available to access translation in live animals as the increase in animals complexity limits the repertoire of experimental tools that could be applied to observe and manipulate processes within animals body, organs, and individual cells. It this study, we developed a labeling-free method for measuring organ- and cell-type specific translation elongation rates. It is based on a time-resolved delivery of translation initiation and elongation inhibitors in live animals followed by ribosome profiling. It also reports translation initiation sites in an organ-specific manner. Using this method, we found that the elongation rates differ among mouse organs and determined them to be 6.8, 5.2, and 4.4 amino acids per sec for liver, kidney, and skeletal muscle, respectively.\n\nSignificanceProtein synthesis is a vital biological process. Modern methods of genome editing enable generation of sophisticated animal models to study the regulation of protein synthesis in health end disease. However, the methods that could track various steps of translation at a gene level resolution in vivo are lacking, particularly in complex vertebrates, such as mice and rats. Here, we measured the translation elongation rate in several organs by delivering inhibitors specific to certain phases of translation directly through the mouse bloodstream. This study lays out a path for interrogating translation in animals in response to various genetic and dietary interventions.

molecular biology↗