EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins i... more EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological...
GTEx simulated expression script. R script to find expected number of overlaps between GTEx tissu... more GTEx simulated expression script. R script to find expected number of overlaps between GTEx tissue DEGs with age when gene names are scrambled.
Evolutionary distance in CellAge genes. PDF with Faith's phylogenetic diversity index of 22 i... more Evolutionary distance in CellAge genes. PDF with Faith's phylogenetic diversity index of 22 individual CellAge genes conserved amongst all 24 mammalian species.
Enriched GO terms as a network generated from genes differentially expressed between AL and CR. (... more Enriched GO terms as a network generated from genes differentially expressed between AL and CR. (PDF 64 kb)
The overlap between genes DE when feeding CR and LA dietary supplementation at 28 months of age w... more The overlap between genes DE when feeding CR and LA dietary supplementation at 28 months of age when compared with AL feeding the non-supplemented diet. It also shows the DAVID enrichment of the overlaps. (XLSX 375 kb)
The 28 longevity genes that have been identified as longevity-associated genes (LAGs) or partners... more The 28 longevity genes that have been identified as longevity-associated genes (LAGs) or partners of LAGs. (XLSX 10 kb)
The transfection efficiencies and viability after transfection with mimics and inhibitors. (XLSX ... more The transfection efficiencies and viability after transfection with mimics and inhibitors. (XLSX 62 kb)
Health and pathologies are multifactorial states characterizing how well biological systems funct... more Health and pathologies are multifactorial states characterizing how well biological systems function in a range of conditions and facing various stressors. Depending on how flexible the definition of a state is, systems may have multiple healthy and stable states. However, keeping homeostasis requires parameters dynamically fluctuating within a physiological range. On the molecular level, states depend on the combined effect of a myriad of genetic, epigenetic and environmental factors, and in response to a time-varying signal from the exposome, the system may transit between states of health, states with better or worse fitness, and disorder states. In this chapter, we discuss how differences in heritable components, repair mechanisms, and exposure to events in early or adult life, influence healthspan, longevity and susceptibility to pathologies. We also review the genomic, methylomic, transcriptomic and metabolomic changes that accumulate with age, and discuss them as potential drivers of shifts towards pathological phenotypes. Lastly, we hypothesize that transitions are generally small and slow during ageing and more dynamic in disease emergence or progression, with both cases being characterized by system-wide changes in the expression and function of their components, the topology of their interactions, and the system’s overall robustness.
If somatic stem cells would be able to maintain their regenerative capacity over time, this might... more If somatic stem cells would be able to maintain their regenerative capacity over time, this might, to a great extent, resolve rejuvenation issues. Unfortunately, the pool of somatic stem cells is limited, and they undergo cell aging with a consequent loss of functionality. During the last decade, low molecular weight compounds that are able to induce or enhance cell reprogramming have been reported. They were named "Small Molecules" (SMs) and might present definite advantages compared to the exogenous introduction of stemness-related transcription factors (e.g. Yamanaka's factors). Here, we undertook a systemic analysis of SMs and their potential gene targets. Data mining and curation lead to the identification of 92 SMs. The SM targets fall into three major functional categories: epigenetics, cell signaling, and metabolic "switchers". All these categories appear to be required in each SM cocktail to induce cell reprogramming. Remarkably, many enriched pathways of SM targets are related to aging, longevity, and age-related diseases, thus connecting them with cell reprogramming. The network analysis indicates that SM targets are highly interconnected and form protein-protein networks of a scale-free topology. The extremely high contribution of hubs to network connectivity suggests that (i) cell reprogramming may require SM targets to act cooperatively, and (ii) their network organization might ensure robustness by resistance to random failures. All in all, further investigation of SMs and their relationship with longevity regulators will be helpful for developing optimal SM cocktails for cell reprogramming with a perspective for rejuvenation and life span extension.
Dysregulation of intercellular communication is a well-established hallmark of aging. To better u... more Dysregulation of intercellular communication is a well-established hallmark of aging. To better understand how this process contributes to the aging phenotype, we built scAgeCom, a comprehensive atlas presenting how cell-type to cell-type interactions vary with age in 23 mouse tissues. We first created an R package, scDiffCom, designed to perform differential intercellular communication analysis between two conditions of interest in any mouse or human single-cell RNA-seq dataset. The package relies on its own list of curated ligand-receptor interactions compiled from seven established studies. We applied this tool to single-cell transcriptomics data from the Tabula Muris Senis consortium and the Calico murine aging cell atlas. All the results can be accessed online, using a user-friendly, interactive web application (https://scagecom.org). The most widespread changes we observed include upregulation of immune system processes, inflammation and lipid metabolism, and downregulation of...
Genetic manipulations can ameliorate the aging process and extend the lifespan of model organisms... more Genetic manipulations can ameliorate the aging process and extend the lifespan of model organisms. The aim of this research was to identify novel genetic interventions that promote both lifespan and healthspan, by combining the effects of multiple longevity-associated gene inactivations in C. elegans. For this, the individual and combined effects of the odr-3 mutation and of ife-2 and cku-70 knock-downs were studied, both in the wild type and daf-16 mutant backgrounds. We found that besides increasing the lifespan of wild type animals, the knock-down of ife-2 (starting at L4) also extends the lifespan and healthspan of long-lived odr-3 mutants. In the daf-16 background, ife-2 and odr-3 impairment exert opposing effects individually, while the daf-16; odr-3; ife-2 deficient animals show a similar lifespan and healthspan as daf-16, suggesting that the odr-3 and ife-2 effector outcomes converge downstream of DAF-16. By contrast, cku-70 knock-down did not extend the lifespan of single or double odr-3; ife-2 inactivated animals, and was slightly deleterious to healthspan. In conclusion, we report that impairment of odr-3 and ife-2 increases lifespan and healthspan in an additive and synergistic manner, respectively, and that this result is not improved by further knocking-down cku-70.
Background Cellular senescence, a permanent state of replicative arrest in otherwise proliferatin... more Background Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking. Results We develop CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological proce...
EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins i... more EDEM-1, EDEM-2 and EDEM-3 are key players for the quality control of newly synthesized proteins in the endoplasmic reticulum (ER) by accelerating disposal and degradation of misfolded proteins through ER Associated Degradation (ERAD). Although many previous studies reported the role of individual ERAD components especially in cell-based systems, still little is known about the consequences of ERAD dysfunction under physiological and ER stress conditions in the context of a multicellular organism. Here we report the first individual and combined characterization and functional interplay of EDEM proteins in Caenorhabditis elegans using single, double, and triple mutant combinations. We found that EDEM-2 has a major role in the clearance of misfolded proteins from ER under physiological conditions, whereas EDEM-1 and EDEM-3 roles become prominent under acute ER stress. In contrast to SEL-1 loss, the loss of EDEMs in an intact organism induces only a modest ER stress under physiological...
GTEx simulated expression script. R script to find expected number of overlaps between GTEx tissu... more GTEx simulated expression script. R script to find expected number of overlaps between GTEx tissue DEGs with age when gene names are scrambled.
Evolutionary distance in CellAge genes. PDF with Faith's phylogenetic diversity index of 22 i... more Evolutionary distance in CellAge genes. PDF with Faith's phylogenetic diversity index of 22 individual CellAge genes conserved amongst all 24 mammalian species.
Enriched GO terms as a network generated from genes differentially expressed between AL and CR. (... more Enriched GO terms as a network generated from genes differentially expressed between AL and CR. (PDF 64 kb)
The overlap between genes DE when feeding CR and LA dietary supplementation at 28 months of age w... more The overlap between genes DE when feeding CR and LA dietary supplementation at 28 months of age when compared with AL feeding the non-supplemented diet. It also shows the DAVID enrichment of the overlaps. (XLSX 375 kb)
The 28 longevity genes that have been identified as longevity-associated genes (LAGs) or partners... more The 28 longevity genes that have been identified as longevity-associated genes (LAGs) or partners of LAGs. (XLSX 10 kb)
The transfection efficiencies and viability after transfection with mimics and inhibitors. (XLSX ... more The transfection efficiencies and viability after transfection with mimics and inhibitors. (XLSX 62 kb)
Health and pathologies are multifactorial states characterizing how well biological systems funct... more Health and pathologies are multifactorial states characterizing how well biological systems function in a range of conditions and facing various stressors. Depending on how flexible the definition of a state is, systems may have multiple healthy and stable states. However, keeping homeostasis requires parameters dynamically fluctuating within a physiological range. On the molecular level, states depend on the combined effect of a myriad of genetic, epigenetic and environmental factors, and in response to a time-varying signal from the exposome, the system may transit between states of health, states with better or worse fitness, and disorder states. In this chapter, we discuss how differences in heritable components, repair mechanisms, and exposure to events in early or adult life, influence healthspan, longevity and susceptibility to pathologies. We also review the genomic, methylomic, transcriptomic and metabolomic changes that accumulate with age, and discuss them as potential drivers of shifts towards pathological phenotypes. Lastly, we hypothesize that transitions are generally small and slow during ageing and more dynamic in disease emergence or progression, with both cases being characterized by system-wide changes in the expression and function of their components, the topology of their interactions, and the system’s overall robustness.
If somatic stem cells would be able to maintain their regenerative capacity over time, this might... more If somatic stem cells would be able to maintain their regenerative capacity over time, this might, to a great extent, resolve rejuvenation issues. Unfortunately, the pool of somatic stem cells is limited, and they undergo cell aging with a consequent loss of functionality. During the last decade, low molecular weight compounds that are able to induce or enhance cell reprogramming have been reported. They were named "Small Molecules" (SMs) and might present definite advantages compared to the exogenous introduction of stemness-related transcription factors (e.g. Yamanaka's factors). Here, we undertook a systemic analysis of SMs and their potential gene targets. Data mining and curation lead to the identification of 92 SMs. The SM targets fall into three major functional categories: epigenetics, cell signaling, and metabolic "switchers". All these categories appear to be required in each SM cocktail to induce cell reprogramming. Remarkably, many enriched pathways of SM targets are related to aging, longevity, and age-related diseases, thus connecting them with cell reprogramming. The network analysis indicates that SM targets are highly interconnected and form protein-protein networks of a scale-free topology. The extremely high contribution of hubs to network connectivity suggests that (i) cell reprogramming may require SM targets to act cooperatively, and (ii) their network organization might ensure robustness by resistance to random failures. All in all, further investigation of SMs and their relationship with longevity regulators will be helpful for developing optimal SM cocktails for cell reprogramming with a perspective for rejuvenation and life span extension.
Dysregulation of intercellular communication is a well-established hallmark of aging. To better u... more Dysregulation of intercellular communication is a well-established hallmark of aging. To better understand how this process contributes to the aging phenotype, we built scAgeCom, a comprehensive atlas presenting how cell-type to cell-type interactions vary with age in 23 mouse tissues. We first created an R package, scDiffCom, designed to perform differential intercellular communication analysis between two conditions of interest in any mouse or human single-cell RNA-seq dataset. The package relies on its own list of curated ligand-receptor interactions compiled from seven established studies. We applied this tool to single-cell transcriptomics data from the Tabula Muris Senis consortium and the Calico murine aging cell atlas. All the results can be accessed online, using a user-friendly, interactive web application (https://scagecom.org). The most widespread changes we observed include upregulation of immune system processes, inflammation and lipid metabolism, and downregulation of...
Genetic manipulations can ameliorate the aging process and extend the lifespan of model organisms... more Genetic manipulations can ameliorate the aging process and extend the lifespan of model organisms. The aim of this research was to identify novel genetic interventions that promote both lifespan and healthspan, by combining the effects of multiple longevity-associated gene inactivations in C. elegans. For this, the individual and combined effects of the odr-3 mutation and of ife-2 and cku-70 knock-downs were studied, both in the wild type and daf-16 mutant backgrounds. We found that besides increasing the lifespan of wild type animals, the knock-down of ife-2 (starting at L4) also extends the lifespan and healthspan of long-lived odr-3 mutants. In the daf-16 background, ife-2 and odr-3 impairment exert opposing effects individually, while the daf-16; odr-3; ife-2 deficient animals show a similar lifespan and healthspan as daf-16, suggesting that the odr-3 and ife-2 effector outcomes converge downstream of DAF-16. By contrast, cku-70 knock-down did not extend the lifespan of single or double odr-3; ife-2 inactivated animals, and was slightly deleterious to healthspan. In conclusion, we report that impairment of odr-3 and ife-2 increases lifespan and healthspan in an additive and synergistic manner, respectively, and that this result is not improved by further knocking-down cku-70.
Background Cellular senescence, a permanent state of replicative arrest in otherwise proliferatin... more Background Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking. Results We develop CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological proce...
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