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 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 Reduced insulin signalling in adulthood protects soma and germline under mutation accumulation

2020 ◽  
Author(s):  
Elizabeth M.L. Duxbury ◽  
Hanne Carlsson ◽  
Kris Sales ◽  
Simone Immler ◽  
Tracey Chapman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Resource Allocation ◽  
Insulin Signalling ◽  
Spontaneous Mutation ◽  
Mutation Accumulation ◽  
Offspring Fitness ◽  
Trade Offs ◽  
Evolutionarily Conserved ◽  
Hidden Cost ◽  
Dominant Theory

AbstractDominant theory maintains that organisms age due to resource allocation trade-offs between the immortal germline and the disposable soma. Strikingly, adulthood-only downregulation of insulin signalling, an evolutionarily conserved pathway regulating resource allocation between reproduction and soma, increases lifespan and offspring fitness without fecundity cost in the nematode, Caenorhabditis elegans. Nevertheless, theory suggests that reduced germline maintenance can be a hidden cost of lifespan extension. We ran a mutation accumulation (MA) experiment and downregulated insulin signalling in half of the 400 MA lines by silencing daf-2 gene expression using RNA interference (RNAi) across 40 generations. Adulthood-only daf-2 RNAi reduced extinction of MA lines both under UV-induced and spontaneous mutation accumulation. Fitness of the surviving UV-induced MA lines was higher under daf-2 RNAi. Our results suggest that reduced insulin signalling protects the soma and the germline and imply that suboptimal gene expression in adulthood is a major driver of organismal ageing.

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 Antagonistically pleiotropic allele increases lifespan and late-life reproduction at the cost of early-life reproduction and individual fitness

2017 ◽  
Vol 284 (1856) ◽  
pp. 20170376 ◽  
Author(s):  
Alexei A. Maklakov ◽  
Hanne Carlsson ◽  
Philip Denbaum ◽  
Martin I. Lind ◽  
Brian Mautz ◽  
...  
Keyword(s):  
Early Life ◽  
Experimental Studies ◽  
Late Life ◽  
Nutrient Sensing ◽  
Loss Of Function ◽  
Individual Fitness ◽  
Offspring Production ◽  
Growth Factor Signalling ◽  
Improved Performance ◽  
Opposing Effects

Evolutionary theory of ageing maintains that increased allocation to early-life reproduction results in reduced somatic maintenance, which is predicted to compromise longevity and late-life reproduction. This prediction has been challenged by the discovery of long-lived mutants with no loss of fecundity. The first such long-lived mutant was found in the nematode worm Caenorhabditis elegans . Specifically, partial loss-of-function mutation in the age-1 gene, involved in the nutrient-sensing insulin/insulin-like growth factor signalling pathway, confers longevity, as well as increased resistance to pathogens and to temperature stress without appreciable fitness detriment. Here, we show that the long-lived age-1 ( hx546 ) mutant has reduced fecundity and offspring production in early-life, but increased fecundity, hatching success, and offspring production in late-life compared with wild-type worms under standard conditions. However, reduced early-life performance of long-lived mutant animals was not fully compensated by improved performance in late-life and resulted in reduced individual fitness. These results suggest that the age-1 ( hx546 ) allele has opposing effects on early-life versus late-life fitness in accordance with antagonistic pleiotropy (AP) and disposable soma theories of ageing. These findings support the theoretical conjecture that experimental studies based on standing genetic variation underestimate the importance of AP in the evolution of ageing.

scholarly journals Intergenerational adaptations to stress are evolutionarily conserved, stress-specific, and have deleterious trade-offs

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Nicholas O Burton ◽  
Alexandra Willis ◽  
Kinsey Fisher ◽  
Fabian Braukmann ◽  
Jonathan Price ◽  
...  
Keyword(s):  
Gene Expression ◽  
Osmotic Stress ◽  
Bacterial Infection ◽  
Parental Stress ◽  
Stress Exposure ◽  
C Elegans ◽  
Trade Offs ◽  
Evolutionarily Conserved ◽  
Physiological Adaptations ◽  
Intergenerational Change

Despite reports of parental exposure to stress promoting physiological adaptations in progeny in diverse organisms, there remains considerable debate over the significance and evolutionary conservation of such multigenerational effects. Here, we investigate four independent models of intergenerational adaptations to stress in C. elegans - bacterial infection, eukaryotic infection, osmotic stress and nutrient stress - across multiple species. We found that all four intergenerational physiological adaptations are conserved in at least one other species, that they are stress-specific, and that they have deleterious trade-offs in mismatched environments. By profiling the effects of parental bacterial infection and osmotic stress exposure on progeny gene expression across species we established a core set of 587 genes that exhibited a greater than 2-fold intergenerational change in expression in response to stress in C. elegans and at least one other species, as well as a set of 37 highly conserved genes that exhibited a greater than 2-fold intergenerational change in expression in all four species tested. Furthermore, we provide evidence suggesting that presumed adaptive and deleterious intergenerational effects are molecularly related at the gene expression level. Lastly, we found that none of the effects we detected of these stresses on C. elegans F1 progeny gene expression persisted transgenerationally three generations after stress exposure. We conclude that intergenerational responses to stress play a substantial and evolutionarily conserved role in regulating animal physiology and that the vast majority of the effects of parental stress on progeny gene expression are reversible and not maintained transgenerationally.

scholarly journals Intergenerational adaptations to stress are evolutionarily conserved, stress-specific, and have deleterious trade-offs

2021 ◽  
Author(s):  
Nick Burton ◽  
Alexandra R Willis ◽  
Kinsey Fisher ◽  
Fabian Braukmann ◽  
Jonathan Price ◽  
...  
Keyword(s):  
Gene Expression ◽  
Osmotic Stress ◽  
Bacterial Infection ◽  
Parental Stress ◽  
Stress Exposure ◽  
Trade Offs ◽  
Evolutionarily Conserved ◽  
Physiological Adaptations ◽  
Conserved Genes ◽  
Multigenerational Effects

Despite reports of parental exposure to stress promoting physiological adaptations in progeny in diverse organisms, there remains considerable debate over the significance and evolutionary conservation of such multigenerational effects. Here, we investigate four independent models of intergenerational adaptations to stress in C. elegans (bacterial infection, eukaryotic infection, osmotic stress and nutrient stress) across multiple species. We found that all four intergenerational physiological adaptations are conserved in at least one other species, that they are stress-specific, and that they have deleterious trade-offs in mismatched environments. By profiling the effects of parental bacterial infection and osmotic stress exposure on progeny gene expression across species we established a core set of 279 highly conserved genes that exhibited intergenerational changes in expression in response to stress in all species tested and provide evidence suggesting that presumed adaptive and deleterious intergenerational effects are molecularly related at the gene expression level. By contrast, we found that these same stresses did not elicit any similarly conserved transgenerational changes in progeny gene expression three generations after stress exposure. We conclude that intergenerational responses to stress play a substantial and evolutionarily conserved role in regulating animal physiology and that the vast majority of the effects of parental stress on progeny gene expression are reversible and not maintained transgenerationally.

scholarly journals Bioenergetics in environmental adaptation and stress tolerance of aquatic ectotherms: linking physiology and ecology in a multi-stressor landscape

2021 ◽  
Vol 224 (Suppl_1) ◽  
Author(s):  
Inna Sokolova
Keyword(s):  
Energy Metabolism ◽  
Environmental Variability ◽  
Multiple Stressors ◽  
Cellular Stress Response ◽  
Trophic Relationships ◽  
Multiple Stressor ◽  
Trade Offs ◽  
Darwinian Fitness ◽  
Energy Trade

ABSTRACT Energy metabolism (encompassing energy assimilation, conversion and utilization) plays a central role in all life processes and serves as a link between the organismal physiology, behavior and ecology. Metabolic rates define the physiological and life-history performance of an organism, have direct implications for Darwinian fitness, and affect ecologically relevant traits such as the trophic relationships, productivity and ecosystem engineering functions. Natural environmental variability and anthropogenic changes expose aquatic ectotherms to multiple stressors that can strongly affect their energy metabolism and thereby modify the energy fluxes within an organism and in the ecosystem. This Review focuses on the role of bioenergetic disturbances and metabolic adjustments in responses to multiple stressors (especially the general cellular stress response), provides examples of the effects of multiple stressors on energy intake, assimilation, conversion and expenditure, and discusses the conceptual and quantitative approaches to identify and mechanistically explain the energy trade-offs in multiple stressor scenarios, and link the cellular and organismal bioenergetics with fitness, productivity and/or ecological functions of aquatic ectotherms.

scholarly journals Adaptive response to a future life challenge: consequences of early-life environmental complexity in dual-purpose chicks

2020 ◽  
Vol 98 (11) ◽  
Author(s):  
Chao Yan ◽  
Kate Hartcher ◽  
Wen Liu ◽  
Jinlong Xiao ◽  
Hai Xiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gut Microbiota ◽  
Early Life ◽  
Plasma Corticosterone ◽  
Adaptive Plasticity ◽  
Environmental Complexity ◽  
Dual Purpose ◽  
Stress Related Genes ◽  
Life Challenge ◽  
Environmental Challenge

Abstract Conditions in early life play profound and long-lasting effects on the welfare and adaptability to stress of chickens. This study aimed to explore the hypothesis that the provision of environmental complexity in early life improves birds’ adaptive plasticity and ability to cope with a challenge later in life. It also tried to investigate the effect of the gut-brain axis by measuring behavior, stress hormone, gene expression, and gut microbiota. One-day-old chicks were split into 3 groups: (1) a barren environment (without enrichment items) group (BG, n = 40), (2) a litter materials group (LG, n = 40), and (3) a perches with litter materials group (PLG, n = 40). Then, enrichment items were removed and simulated as an environmental challenge at 31 to 53 d of age. Birds were subjected to a predator test at 42 d of age. In the environmental challenge, when compared with LG, PLG birds were characterized by decreased fearfulness, lower plasma corticosterone, improved gut microbial functions, lower relative mRNA expression of GR, and elevated mRNA expressions of stress-related genes CRH, BDNF, and NR2A in the hypothalamus (all P < 0.05). Unexpectedly, the opposite was true for the LG birds when compared with the BG (P < 0.05). Decreased plasma corticosterone and fearfulness were accompanied by altered hypothalamic gene mRNA expressions of BDNF, NR2A, GR, and CRH through the HPA axis in response to altered gut microbial compositions and functions. The findings suggest that gut microbiota may integrate fearfulness, plasma corticosterone, and gene expression in the hypothalamus to provide an insight into the gut-brain axis in chicks. In conclusion, having access to both perches and litter materials in early life allowed birds to cope better with a future challenge. Birds in perches and litter materials environment may have optimal development and adaptive plasticity through the gut-brain axis.

scholarly journals Maternal Style Selectively Shapes Amygdalar Development and Social Behavior in Rats Genetically Prone to High Anxiety

2015 ◽  
Vol 37 (3) ◽  
pp. 203-214 ◽  
Author(s):  
Joshua L. Cohen ◽  
Matthew E. Glover ◽  
Phyllis C. Pugh ◽  
Andrew D. Fant ◽  
Rebecca K. Simmons ◽  
...  
Keyword(s):  
Gene Expression ◽  
Psychological Health ◽  
Early Life ◽  
Developmental Trajectory ◽  
Emotional Behavior ◽  
Developmental Gene ◽  
Developmental Gene Expression ◽  
Maternal Style ◽  
Anxiety Depression ◽  
Cross Fostering

The early-life environment critically influences neurodevelopment and later psychological health. To elucidate neural and environmental elements that shape emotional behavior, we developed a rat model of individual differences in temperament and environmental reactivity. We selectively bred rats for high versus low behavioral response to novelty and found that high-reactive (bred high-responder, bHR) rats displayed greater risk-taking, impulsivity and aggression relative to low-reactive (bred low-responder, bLR) rats, which showed high levels of anxiety/depression-like behavior and certain stress vulnerability. The bHR/bLR traits are heritable, but prior work revealed bHR/bLR maternal style differences, with bLR dams showing more maternal attention than bHRs. The present study implemented a cross-fostering paradigm to examine the contribution of maternal behavior to the brain development and emotional behavior of bLR offspring. bLR offspring were reared by biological bLR mothers or fostered to a bLR or bHR mother and then evaluated to determine the effects on the following: (1) developmental gene expression in the hippocampus and amygdala and (2) adult anxiety/depression-like behavior. Genome-wide expression profiling showed that cross-fostering bLR rats to bHR mothers shifted developmental gene expression in the amygdala (but not hippocampus), reduced adult anxiety and enhanced social interaction. Our findings illustrate how an early-life manipulation such as cross-fostering changes the brain's developmental trajectory and ultimately impacts adult behavior. Moreover, while earlier studies highlighted hippocampal differences contributing to the bHR/bLR phenotypes, our results point to a role of the amygdala as well. Future work will pursue genetic and cellular mechanisms within the amygdala that contribute to bHR/bLR behavior either at baseline or following environmental manipulations.

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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