Iron serves as a cofactor for enzymes involved in several steps of protein translation, but the control of translation during iron limitation is not understood at the molecular level. Here, we report ...a genome-wide analysis of protein translation in response to iron deficiency in yeast using ribosome profiling. We show that iron depletion affects global protein synthesis and leads to translational repression of multiple genes involved in iron-related processes. Furthermore, we demonstrate that the RNA-binding proteins Cth1 and Cth2 play a central role in this translational regulation by repressing the activity of the iron-dependent Rli1 ribosome recycling factor and inhibiting mitochondrial translation and heme biosynthesis. Additionally, we found that iron deficiency represses MRS3 mRNA translation through increased expression of antisense long non-coding RNA. Together, our results reveal complex gene expression and protein synthesis remodeling in response to low iron, demonstrating how this important metal affects protein translation at multiple levels.
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•Iron depletion represses translation of genes involved in iron-related processes•Cth1/2 mRNA-binding proteins inhibit mitochondrial translation and heme synthesis•Low iron increases translation in 3′UTRs due to Cth1/2-dependent inhibition of Rli1•MRS3 translation is repressed by low iron through expression of antisense lncRNA
Molecular biology; Transcriptomics
At the cellular level, many aspects of aging are conserved across species. This has been demonstrated by numerous studies in simple model organisms like
Saccharomyces cerevisiae
,
Caenorhabdits ...elegans
, and
Drosophila melanogaster
. Because most genetic screens examine loss of function mutations or decreased expression of genes through reverse genetics, essential genes have often been overlooked as potential modulators of the aging process. By taking the approach of increasing the expression level of a subset of conserved essential genes, we found that 21% of these genes resulted in increased replicative lifespan in
S. cerevisiae
. This is greater than the ~ 3.5% of genes found to affect lifespan upon deletion, suggesting that activation of essential genes may have a relatively disproportionate effect on increasing lifespan. The results of our experiments demonstrate that essential gene overexpression is a rich, relatively unexplored means of increasing eukaryotic lifespan.
The origin of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is the subject of many hypotheses. One of them, proposed by Segreto and Deigin, assumes artificial chimeric construction of ...SARS‐CoV‐2 from a backbone of RaTG13‐like CoV and receptor binding domain (RBD) of a pangolin MP789‐like CoV, followed by serial cell or animal passage. Here we show that this hypothesis relies on incorrect or weak assumptions, and does not agree with the results of comparative genomics analysis. The genetic divergence between SARS‐CoV‐2 and both its proposed ancestors is too high to have accumulated in a lab, given the timeframe of several years. Furthermore, comparative analysis of S‐protein gene sequences suggests that the RBD of SARS‐CoV‐2 probably represents an ancestral non‐recombinant variant. These and other arguments significantly weaken the hypothesis of a laboratory origin for SARS‐CoV‐2, while the hypothesis of a natural origin is consistent with all available genetic and experimental data.
A hypothesis of man‐made SARS‐CoV‐2 origin appeared in the scientific literature. Here we discuss the flaws of this hypothesis and argue that the available comparative genomics data including genetic divergence, distribution of substitution rates, and parsimonious reconstructions of recombination events support a scenario of a natural origin for SARS‐CoV‐2.
The causative agent of COVID‐19 SARS‐CoV‐2 has led to over 4 million deaths worldwide. Understanding the origin of this coronavirus is important for the prevention of future outbreaks. The dominant ...point of view that the virus transferred to humans either directly from bats or through an intermediate mammalian host has been challenged by Segreto and Deigin, who claim that the genome of SARS‐CoV‐2 has certain features suggestive of its artificial creation. Following their response to our commentary, here we continue the discussion of the proposed arguments for this hypothesis. We show that neither the existence of a furin cleavage site in SARS‐CoV‐2, nor the presence of specific sequences within the nucleotide insertion encoding that site are evidence for intelligent design. We also explain why existing genetic data, viral diversity and past human history suggest that a natural origin of the virus is the most likely scenario. Genetic evidence suggesting otherwise is yet to be presented.
Recently discovered bat CoVs share higher genetic similarity with SARS‐CoV‐2, than those previously described. SARS‐CoV‐2 furin site is non‐canonical. The prior probabilities of natural virus origins are higher given past human history and present viral diversity. Other arguments are discussed. The SARS‐CoV‐2 artificial creation hypothesis is not supported by evidence.
Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies ...have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.
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•Biological age undergoes rapid fluctuations in mice and humans•Severe stress induces increases in biological age that are reversed upon recovery•Parabiosis, surgery, pregnancy, and COVID-19 transiently elevate biological age•Biological age recovery rate may predict gerotherapeutics
Poganik et al. analyzed various models of severe stress in mice and humans and found that stress transiently elevates biological age as readout by multiple advanced biomarkers of aging. They demonstrate that biological age is not static, but dynamic.
Several pharmacological, dietary, and genetic interventions that increase mammalian lifespan are known, but general principles of lifespan extension remain unclear. Here, we performed RNA sequencing ...(RNA-seq) analyses of mice subjected to 8 longevity interventions. We discovered a feminizing effect associated with growth hormone regulation and diminution of sex-related differences. Expanding this analysis to 17 interventions with public data, we observed that many interventions induced similar gene expression changes. We identified hepatic gene signatures associated with lifespan extension across interventions, including upregulation of oxidative phosphorylation and drug metabolism, and showed that perturbed pathways may be shared across tissues. We further applied the discovered longevity signatures to identify new lifespan-extending candidates, such as chronic hypoxia, KU-0063794, and ascorbyl-palmitate. Finally, we developed GENtervention, an app that visualizes associations between gene expression changes and longevity. Overall, this study describes general and specific transcriptomic programs of lifespan extension in mice and provides tools to discover new interventions.
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•Sex-specific differences are decreased in response to longevity interventions•Many interventions, but not rapamycin, exhibit similar transcriptomic responses•Certain gene expression changes are associated with longevity across interventions•Longevity signatures may be used to discover new lifespan-extending interventions
Tyshkovskiy et al. performed a comprehensive analysis of 17 known lifespan-extending interventions in mice at the level of gene expression to better understand general principles of lifespan control and generate gene expression signatures associated with longevity. They applied these signatures to predict new candidate compounds for lifespan extension.
Abundant high-molecular-mass hyaluronic acid (HMM-HA) contributes to cancer resistance and possibly to the longevity of the longest-lived rodent-the naked mole-rat
. To study whether the benefits of ...HMM-HA could be transferred to other animal species, we generated a transgenic mouse overexpressing naked mole-rat hyaluronic acid synthase 2 gene (nmrHas2). nmrHas2 mice showed an increase in hyaluronan levels in several tissues, and a lower incidence of spontaneous and induced cancer, extended lifespan and improved healthspan. The transcriptome signature of nmrHas2 mice shifted towards that of longer-lived species. The most notable change observed in nmrHas2 mice was attenuated inflammation across multiple tissues. HMM-HA reduced inflammation through several pathways, including a direct immunoregulatory effect on immune cells, protection from oxidative stress and improved gut barrier function during ageing. These beneficial effects were conferred by HMM-HA and were not specific to the nmrHas2 gene. These findings demonstrate that the longevity mechanism that evolved in the naked mole-rat can be exported to other species, and open new paths for using HMM-HA to improve lifespan and healthspan.
AgeMeta is a database that provides systemic and quantitative description of mammalian aging at the level of gene expression. It encompasses transcriptomic changes with age across various tissues of ...humans, mice, and rats, based on a comprehensive meta-analysis of 122 publicly available gene expression datasets from 26 studies. AgeMeta provides an intuitive visual interface for quantification of aging-associated transcriptomics at the level of individual genes and functional groups of genes, allowing easy comparison among various species and tissues. Additionally, all the data in the database can be downloaded and analyzed independently. Overall, this work contributes to the understanding of the complex network of biological processes underlying mammalian aging and supports future advancements in this field. AgeMeta is freely available at:
https://age-meta.com/
.
Graphic abstract
Lifespan varies within and across species, but the general principles of its control remain unclear. Here, we conducted multi-tissue RNA-seq analyses across 41 mammalian species, identifying ...longevity signatures and examining their relationship with transcriptomic biomarkers of aging and established lifespan-extending interventions. An integrative analysis uncovered shared longevity mechanisms within and across species, including downregulated Igf1 and upregulated mitochondrial translation genes, and unique features, such as distinct regulation of the innate immune response and cellular respiration. Signatures of long-lived species were positively correlated with age-related changes and enriched for evolutionarily ancient essential genes, involved in proteolysis and PI3K-Akt signaling. Conversely, lifespan-extending interventions counteracted aging patterns and affected younger, mutable genes enriched for energy metabolism. The identified biomarkers revealed longevity interventions, including KU0063794, which extended mouse lifespan and healthspan. Overall, this study uncovers universal and distinct strategies of lifespan regulation within and across species and provides tools for discovering longevity interventions.
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•Distinct molecular mechanisms control lifespan within and across species•Aging effects are reversed by longevity interventions but not by species longevity•Regulation of Igf1 and mitochondrial translation are shared signatures of longevity•Longevity signatures enable the discovery of geroprotectors, such as KU0063794
The analysis of multi-tissue gene expression signatures associated with longevity across mammalian species and their interaction with biomarkers of aging and signatures of lifespan-extending interventions reveals universal and distinct strategies of lifespan regulation within and across species and provides tools for the discovery of longevity interventions in mammals.
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