scholarly journals Cost-free lifespan extension via optimisation of gene expression in adulthood supports the developmental theory of ageing

2019 ◽  
Author(s):  
Martin I. Lind ◽  
Hanne Carlsson ◽  
Edward Ivimey-Cook ◽  
Alexei A. Maklakov
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Reproductive Period ◽  
Developmental Theory ◽  
Nutrient Sensing ◽  
Selection Gradients ◽  
Trade Offs ◽  
Global Protein Synthesis ◽  
Longevity Genes ◽  
Energy Trade

SummaryClassic theory upholds that energy trade-offs between reproduction and somatic maintenance underpin the evolution of ageing and lifespan. In contrast, the developmental theory of ageing (DTA) suggests that organismal senescence is caused by dysregulated gene expression in adulthood due to decline in selection gradients with age. The DTA predicts that age-specific optimisation of gene expression can improve survival without fitness costs. Here we investigated consequences for survival, reproduction, egg size and fitness of early-life, adulthood and post-reproductive onset of RNAi knockdown of five well-described “longevity” genes involved in key biological processes in Caenorhabditis elegans nematodes: nutrient-sensing signalling via insulin/IGF-1 (age-1) and target-of-rapamycin (raga-1) pathways, global protein synthesis (ifg-1), global protein synthesis in somatic cells (ife-2) and mitochondrial respiration (nuo-6). Downregulation of these genes in adulthood and/or during post-reproductive period improves survival, while there was little evidence for a link between impaired reproduction and extended lifespan. Our findings demonstrate that hyper-function of diverse physiological processes after sexual maturation is detrimental for survival. Therefore, optimisation of gene expression in adult organisms can ameliorate ageing and increase fitness.

scholarly journals Experimentally reduced insulin/IGF-1 signalling in adulthood extends lifespan of parents and improves Darwinian fitness of their offspring

2018 ◽  
Author(s):  
Martin I. Lind ◽  
Sanjana Ravindran ◽  
Zuzana Sekajova ◽  
Hanne Carlsson ◽  
Andrea Hinas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Early Life ◽  
Late Life ◽  
Nutrient Sensing ◽  
Cellular Damage ◽  
Offspring Fitness ◽  
Trade Offs ◽  
Darwinian Fitness ◽  
Evolutionarily Conserved ◽  
Energy Trade

AbstractClassical theory maintains that ageing evolves via energy trade-offs between reproduction and survival leading to accumulation of unrepaired cellular damage with age. In contrast, the emerging new theory postulates that ageing evolves because of deleterious late-life hyper-function of reproduction-promoting genes leading to excessive biosynthesis in late-life. The hyper-function theory uniquely predicts that optimizing nutrient-sensing molecular signalling in adulthood can simultaneously postpone ageing and increase Darwinian fitness. Here we show that reducing evolutionarily conserved insulin/IGF-1 nutrient-sensing signalling via daf-2 RNA interference (RNAi) fulfils this prediction in Caenorhabditis elegans nematodes. Long-lived daf-2 RNAi parents showed normal fecundity as self-fertilizing hermaphrodites and improved late-life reproduction when mated to males. Remarkably, the offspring of daf-2 RNAi parents had higher Darwinian fitness across three different genotypes. Thus, reduced nutrient-sensing signalling in adulthood improves both parental longevity and offspring fitness supporting the emerging view that sub-optimal gene expression in late-life lies at the heart of ageing.Impact StatementUnderstanding mechanisms underpinning ageing is fundamental to improving quality of life in an increasingly long-lived society. Recent breakthroughs have challenged the long-standing paradigm that the energy trade-off between reproduction and somatic maintenance causes organismal senescence via slow accumulation of unrepaired cellular damage with age. The emerging new theory of ageing provides a conceptually novel framework by proposing that ageing is a direct consequence of physiological processes optimized for early-life function, such as growth and early-life reproduction, that are running ‘too high’ (i.e. at hyperfunction) in late adulthood. Contrary to the classic view based on damage accumulation, the hyperfunction theory proposes that suboptimal gene expression in late-life causes ageing via excessive biosynthesis. Thus, the hyperfunction theory uniquely predicts that longevity and Darwinian fitness can be simultaneously increased by reducing unnecessarily high levels of nutrient-sensing signalling in adulthood. Here we show that reducing evolutionarily conserved nutrient-sensing signalling pathway fulfils this prediction in Caenorhabditis elegans nematodes. We found that downregulation of the insulin/IGF-1 signalling in adult C. elegans nematodes not only improves longevity but, most intriguingly, increases fitness of the resulting offspring in the next generation. We found support for increase in offspring fitness across different genetic backgrounds. Our findings contradict the theoretical conjecture that energy trade-offs between growth, reproduction and longevity is the universal cause of senescence and provide strong experimental support for the emerging hyperfunction theory of ageing.

scholarly journals Cost-free lifespan extension via optimization of gene expression in adulthood aligns with the developmental theory of ageing

2021 ◽  
Vol 288 (1944) ◽  
pp. 20201728
Author(s):  
Martin I. Lind ◽  
Hanne Carlsson ◽  
Elizabeth M. L. Duxbury ◽  
Edward Ivimey-Cook ◽  
Alexei A. Maklakov
Keyword(s):  
Gene Expression ◽  
Resource Allocation ◽  
Life Histories ◽  
Reproductive Period ◽  
Developmental Theory ◽  
Somatic Maintenance ◽  
Individual Fitness ◽  
Longevity Genes ◽  
Extended Lifespan ◽  
Reproduction Costs

Ageing evolves because the force of selection on traits declines with age but the proximate causes of ageing are incompletely understood. The ‘disposable soma’ theory of ageing (DST) upholds that competitive resource allocation between reproduction and somatic maintenance underpins the evolution of ageing and lifespan. In contrast, the developmental theory of ageing (DTA) suggests that organismal senescence is caused by suboptimal gene expression in adulthood. While the DST predicts the trade-off between reproduction and lifespan, the DTA predicts that age-specific optimization of gene expression can increase lifespan without reproduction costs. Here we investigated the consequences for lifespan, reproduction, egg size and individual fitness of early-life, adulthood and post-reproductive onset of RNAi knockdown of five ‘longevity’ genes involved in key biological processes in Caenorhabditis elegans . Downregulation of these genes in adulthood and/or during post-reproductive period increases lifespan, while we found limited evidence for a link between impaired reproduction and extended lifespan. Our findings demonstrate that suboptimal gene expression in adulthood often contributes to reduced lifespan directly rather than through competitive resource allocation between reproduction and somatic maintenance. Therefore, age-specific optimization of gene expression in evolutionarily conserved signalling pathways that regulate organismal life histories can increase lifespan without fitness costs.

scholarly journals Anabolic Function Downstream of TOR Controls Trade-offs Between Longevity and Reproduction at the Level of Specific Tissues in C. elegans

2021 ◽  
Vol 2 ◽  
Author(s):  
Amber C. Howard ◽  
Dilawar Mir ◽  
Santina Snow ◽  
Jordan Horrocks ◽  
Hussein Sayed ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Energy Expenditure ◽  
Dietary Restriction ◽  
Nutrient Sensing ◽  
Whole Body ◽  
C Elegans ◽  
Positive Effects ◽  
Body Muscle ◽  
Trade Offs ◽  
Different Tissues

As the most energetically expensive cellular process, translation must be finely tuned to environmental conditions. Dietary restriction attenuates signaling through the nutrient sensing mTOR pathway, which reduces translation and redirects resources to preserve the soma. These responses are associated with increased lifespan but also anabolic impairment, phenotypes also observed when translation is genetically suppressed. Here, we restricted translation downstream of mTOR separately in major tissues in C. elegans to better understand their roles in systemic adaptation and whether consequences to anabolic impairment were separable from positive effects on lifespan. Lowering translation in neurons, hypodermis, or germline tissue led to increased lifespan under well-fed conditions and improved survival upon withdrawal of food, indicating that these are key tissues coordinating enhanced survival when protein synthesis is reduced. Surprisingly, lowering translation in body muscle during development shortened lifespan while accelerating and increasing reproduction, a reversal of phenotypic trade-offs associated with systemic translation suppression. Suppressing mTORC1 selectively in body muscle also increased reproduction while slowing motility during development. In nature, this may be indicative of reduced energy expenditure related to foraging, acting as a “GO!” signal for reproduction. Together, results indicate that low translation in different tissues helps direct distinct systemic adaptations and suggest that unknown endocrine signals mediate these responses. Furthermore, mTOR or translation inhibitory therapeutics that target specific tissues may achieve desired interventions to aging without loss of whole-body anabolism.

scholarly journals Evolution of ageing as a tangle of trade-offs: energy versus function

2019 ◽  
Vol 286 (1911) ◽  
pp. 20191604 ◽  
Author(s):  
Alexei A. Maklakov ◽  
Tracey Chapman
Keyword(s):  
Gene Expression ◽  
Early Life ◽  
Regulation Of Gene Expression ◽  
Late Life ◽  
Cellular Damage ◽  
Future Research ◽  
Relative Contribution ◽  
Trade Offs ◽  
Energy Trade ◽  
And Function

Despite tremendous progress in recent years, our understanding of the evolution of ageing is still incomplete. A dominant paradigm maintains that ageing evolves due to the competing energy demands of reproduction and somatic maintenance leading to slow accumulation of unrepaired cellular damage with age. However, the centrality of energy trade-offs in ageing has been increasingly challenged as studies in different organisms have uncoupled the trade-off between reproduction and longevity. An emerging theory is that ageing instead is caused by biological processes that are optimized for early-life function but become harmful when they continue to run-on unabated in late life. This idea builds on the realization that early-life regulation of gene expression can break down in late life because natural selection is too weak to optimize it. Empirical evidence increasingly supports the hypothesis that suboptimal gene expression in adulthood can result in physiological malfunction leading to organismal senescence. We argue that the current state of the art in the study of ageing contradicts the widely held view that energy trade-offs between growth, reproduction, and longevity are the universal underpinning of senescence. Future research should focus on understanding the relative contribution of energy and function trade-offs to the evolution and expression of ageing.

scholarly journals Vasohibin1, a new IRES trans-acting factor for induction of (lymph)angiogenic factors in early hypoxia

2018 ◽  
Author(s):  
Fransky Hantelys ◽  
Anne-Claire Godet ◽  
Florian David ◽  
Florence Tatin ◽  
Edith Renaud-Gabardos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Growth Factors ◽  
Ischemic Heart ◽  
Transcriptional Level ◽  
Angiogenic Growth Factors ◽  
Internal Ribosome Entry ◽  
Global Protein Synthesis ◽  
Specific Mrnas ◽  
Angiogenic Genes

ABSTRACTHypoxia, a major inducer of angiogenesis, is known to trigger major changes of gene expression at the transcriptional level. Furthermore, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 cardiomyocytes: most genes are not induced at the transcriptome-, but at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) able to activate FGF1 and VEGFD IRESs in hypoxia while it inhibits several IRESs in normoxia. Thus this new ITAF may have opposite effects on IRES activities. These data suggest a generalized process of IRES-dependent translational induction of (lymph)angiogenic growth factors expression in early hypoxia, whose pathophysiological relevance is to trigger formation of new functional vessels in ischemic heart. VASH1 is not always required, indicating that the IRESome composition is variable, thus allowing subgroups of IRESs to be activated under the control of different ITAFs.

scholarly journals Vasohibin1, a new mouse cardiomyocyte IRES trans-acting factor that regulates translation in early hypoxia

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Fransky Hantelys ◽  
Anne-Claire Godet ◽  
Florian David ◽  
Florence Tatin ◽  
Edith Renaud-Gabardos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Translational Control ◽  
Ischemic Heart ◽  
Angiogenic Factor ◽  
Transcriptional Level ◽  
Internal Ribosome Entry ◽  
Global Protein Synthesis ◽  
Specific Mrnas ◽  
Angiogenic Genes

Hypoxia, a major inducer of angiogenesis, triggers major changes in gene expression at the transcriptional level. Furthermore, under hypoxia, global protein synthesis is blocked while internal ribosome entry sites (IRES) allow specific mRNAs to be translated. Here, we report the transcriptome and translatome signatures of (lymph)angiogenic genes in hypoxic HL-1 mouse cardiomyocytes: most genes are induced at the translatome level, including all IRES-containing mRNAs. Our data reveal activation of (lymph)angiogenic factor mRNA IRESs in early hypoxia. We identify vasohibin1 (VASH1) as an IRES trans-acting factor (ITAF) that is able to bind RNA and to activate the FGF1 IRES in hypoxia, but which tends to inhibit several IRESs in normoxia. VASH1 depletion has a wide impact on the translatome of (lymph)angiogenesis genes, suggesting that this protein can regulate translation positively or negatively in early hypoxia. Translational control thus appears as a pivotal process triggering new vessel formation in ischemic heart.

scholarly journals Robust and precise morphogen-mediated patterning: trade-offs, constraints and mechanisms

2015 ◽  
Vol 12 (102) ◽  
pp. 20141041 ◽  
Author(s):  
Wing-Cheong Lo ◽  
Shaohua Zhou ◽  
Frederic Y.-M. Wan ◽  
Arthur D. Lander ◽  
Qing Nie
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Steady State ◽  
Cell Surface ◽  
Morphogen Gradients ◽  
Environmental Perturbations ◽  
Trade Offs ◽  
Accuracy And Precision ◽  
Wing Discs ◽  
Cell To Cell Variability

The patterning of many developing tissues is organized by morphogens. Genetic and environmental perturbations of gene expression, protein synthesis and ligand binding are among the sources of unreliability that limit the accuracy and precision of morphogen-mediated patterning. While it has been found that the robustness of morphogen gradients to the perturbation of morphogen synthesis can be enhanced by particular mechanisms, how such mechanisms affect robustness to other perturbations, such as to receptor synthesis for the same morphogen, has been little explored. Here, we investigate the interplay between the robustness of patterning to the changes in receptor synthesis and morphogen synthesis and to the effects of cell-to-cell variability. Our analysis elucidates the trade-offs and constraints that arise as a result of achieving these three performance objectives simultaneously in the context of simple, steady-state morphogen gradients formed by diffusion and receptor-mediated uptake. Analysis of the interdependence between length scales of patterning and these performance objectives reveals several potential mechanisms for mitigating such trade-offs and constraints. One involves downregulation of receptor synthesis in the morphogen source, while another involves the presence of non-signalling cell-surface morphogen-binding molecules. Both of these mechanisms occur in Drosophila wing discs during their patterning. We computationally elucidate how these mechanisms improve the robustness and precision of morphogen-mediated patterning.

tiRNAs & tRFs Biogenesis and Regulation of Diseases: A Review

2019 ◽  
Vol 26 (31) ◽  
pp. 5849-5861 ◽  
Author(s):  
Pan Jiang ◽  
Feng Yan
Keyword(s):  
Gene Expression ◽  
Protein Synthesis ◽  
Metabolic Diseases ◽  
Viral Infections ◽  
Regulatory Mechanisms ◽  
Biological Functions ◽  
Reverse Transcriptases ◽  
Dna Damage Responses ◽  
Potential Applications ◽  
Viral Reverse Transcriptases

tiRNAs & tRFs are a class of small molecular noncoding tRNA derived from precise processing of mature or precursor tRNAs. Most tiRNAs & tRFs described originate from nucleus-encoded tRNAs, and only a few tiRNAs and tRFs have been reported. They have been suggested to play important roles in inhibiting protein synthesis, regulating gene expression, priming viral reverse transcriptases, and the modulation of DNA damage responses. However, the regulatory mechanisms and potential function of tiRNAs & tRFs remain poorly understood. This review aims to describe tiRNAs & tRFs, including their structure, biological functions and subcellular localization. The regulatory roles of tiRNAs & tRFs in translation, neurodegeneration, metabolic diseases, viral infections, and carcinogenesis are also discussed in detail. Finally, the potential applications of these noncoding tRNAs as biomarkers and gene regulators in different diseases is also highlighted.

scholarly journals Gene Expression Space Shapes the Bioprocess Trade-Offs among Titer, Yield and Productivity

2021 ◽  
Vol 11 (13) ◽  
pp. 5859
Author(s):  
Fernando N. Santos-Navarro ◽  
Yadira Boada ◽  
Alejandro Vignoni ◽  
Jesús Picó
Keyword(s):  
Gene Expression ◽  
Gene Transcription ◽  
Performance Metrics ◽  
Cell Mass ◽  
Gene Copy ◽  
Substrate Uptake ◽  
Promoter Strength ◽  
Expression Levels ◽  
Trade Offs ◽  
Wide Range

Optimal gene expression is central for the development of both bacterial expression systems for heterologous protein production, and microbial cell factories for industrial metabolite production. Our goal is to fulfill industry-level overproduction demands optimally, as measured by the following key performance metrics: titer, productivity rate, and yield (TRY). Here we use a multiscale model incorporating the dynamics of (i) the cell population in the bioreactor, (ii) the substrate uptake and (iii) the interaction between the cell host and expression of the protein of interest. Our model predicts cell growth rate and cell mass distribution between enzymes of interest and host enzymes as a function of substrate uptake and the following main lab-accessible gene expression-related characteristics: promoter strength, gene copy number and ribosome binding site strength. We evaluated the differential roles of gene transcription and translation in shaping TRY trade-offs for a wide range of expression levels and the sensitivity of the TRY space to variations in substrate availability. Our results show that, at low expression levels, gene transcription mainly defined TRY, and gene translation had a limited effect; whereas, at high expression levels, TRY depended on the product of both, in agreement with experiments in the literature.

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