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Stress resistance of wild-type C. elegans and aging mutants during larval development. Twenty to forty eggs per plate from two to three egg-laying worms were collected and exposed to UV or grown on plates containing paraquat. The developmental stage of each worm on each plate was recorded throughout development. (A) Larval development of UV-irradiated eggs. (B) Larval development on paraquat-containing plates. Each experiment was repeated 3–4 times.
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DNA repair is an important mechanism by which cells maintain genomic integrity. Decline in DNA repair capacity or defects
in repair factors are thought to contribute to premature aging in mammals. The nematode Caenorhabditis elegans is a good model for studying longevity and DNA repair because of key advances in understanding the genetics of aging...
Citations
... Hence, when these pathways are inactive, an organism transitions to a conserving state until food becomes available again. Inactivating them stimulates DNA repair mechanisms, increases resistance to reactive oxygen species and strengthens protein homeostasis (Chávez et al., 2007;Conn & Qian, 2011;Hyun et al., 2008). One way to maintain protein homeostasis is autophagy, a process that recycles non-functional proteins and organelles (Y. ...
The upcoming phase of space exploration not only includes trips to Mars and beyond, but also holds great promise for human progress. However, the vulnerability of space habitats to cosmic radiation, which consists of Galactic Cosmic Rays and Solar Particle Events, raises important safety concerns for astronauts and other living things that will accompany them. Research exploring the biological effects of cosmic radiation consists of experiments conducted in space itself and in simulated space environments on Earth. Notably, NASA's Space Radiation Laboratory has taken significant steps forward in simulating cosmic radiation by using particle accelerators, marking a notable advancement in this field. Intriguingly, much of the research emphasis thus far has been on understanding how cosmic radiation impacts living organisms, instead of finding ways to help them resist the radiation. In this paper, we briefly talk about current research on the biological effects of cosmic radiation and propose possible protective measures through biological interventions. In our opinion, biological pathways responsible for coping with stressors on Earth offer potential solutions for protection against the stress caused by cosmic radiation. Additionally, we recommend assessing the effectiveness of these pathways through experiments using particle accelerators to simulate the effects of cosmic radiation.
... Thus, compound-specific effects suggest age-dependent dysfunction of the complex repair process of HN2-induced DNA crosslinks, although this has yet to be determined. Importantly, the DNA repair capacity has been shown to correlate with C. elegans longevity [69,70]. Alternatively, HN2-induced ICLs may have a stronger toxic effect due to their negative impact on gene transcription, since transcriptional elongation speed has been shown to increase with age [71]. ...
Caenorhabditis elegans (C. elegans) is gaining recognition and importance as an organismic model for toxicity testing in line with the 3Rs principle (replace, reduce, refine). In this study, we explored the use of C. elegans to examine the toxicities of alkylating sulphur mustard analogues, specifically the monofunctional agent 2-chloroethyl-ethyl sulphide (CEES) and the bifunctional, crosslinking agent mechlorethamine (HN2). We exposed wild-type worms at different life cycle stages (from larvae L1 to adulthood day 10) to CEES or HN2 and scored their viability 24 h later. The susceptibility of C. elegans to CEES and HN2 paralleled that of human cells, with HN2 exhibiting higher toxicity than CEES, reflected in LC 50 values in the high µM to low mM range. Importantly, the effects were dependent on the worms' developmental stage as well as organismic age: the highest susceptibility was observed in L1, whereas the lowest was observed in L4 worms. In adult worms, susceptibility to alkylating agents increased with advanced age, especially to HN2. To examine reproductive effects, L4 worms were exposed to CEES and HN2, and both the offspring and the percentage of unhatched eggs were assessed. Moreover, germline apoptosis was assessed by using ced-1p::GFP (MD701) worms. In contrast to concentrations that elicited low toxicities to L4 worms, CEES and HN2 were highly toxic to germline cells, manifesting as increased germline apoptosis as well as reduced offspring number and percentage of eggs hatched. Again, HN2 exhibited stronger effects than CEES. Compound specificity was also evident in toxicities to dopaminergic neurons-HN2 exposure affected expression of dopamine transporter DAT-1 (strain BY200) at lower concentrations than CEES, suggesting a higher neurotoxic effect. Mechanistically, nicotinamide adenine dinucleotide (NAD +) has been linked to mustard agent toxicities. Therefore, the NAD +-dependent system was investigated in the response to CEES and HN2 treatment. Overall NAD + levels in worm extracts were revealed to be largely resistant to mustard exposure except for high concentrations, which lowered the NAD + levels in L4 worms 24 h post-treatment. Interestingly, however, mutant worms lacking components of NAD +-dependent pathways involved in genome maintenance, namely pme-2, parg-2, and sirt-2.1 showed a higher and compound-specific susceptibility, indicating an active role of NAD + in genotoxic stress response. In conclusion, the present results demonstrate that C. elegans represents an attractive model to study the toxicology of alkylating agents, which supports its use in mechanistic as well as intervention studies with major strength in the possibility to analyze toxicities at different life cycle stages.
... The first age-regulating genes were identified in C. elegans [35,42,64]. Through the lens of the Hallmarks of Aging [77], genome instability [47,99], epigenetic changes [39,75,88], disrupted proteostasis [137,153], disabled macroautophagy [7,86], deregulated nutrient-sensing [48,56,139], mitochondrial dysfunction [13,27], stem cell exhaustion [70,135], altered intercellular communication [45,89], and dysbiosis [41,124] all contribute to establishing lifespan. Numerous evolutionarily conserved cellular and molecular mechanisms drive aging from worms to mammals. ...
Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals. C. elegans is a powerful model system for this type of drug discovery. Combined with automated data capture and analysis technologies, truly high-throughput longevity drug discovery is possible. In this perspective, we propose the "million-molecule challenge", an effort to quantitatively assess 1,000,000 interventions for longevity within five years. The WormBot-AI, our best-in-class robotics and AI data analysis platform, provides a tool to achieve the million-molecule challenge for pennies per animal tested.
... Several papers have been published on the effects of 254-UVC irradiation on nematodes [23,41,42]. In addition, the amount of CPD produced in vivo by nematode 254-UVC irradiation has also been investigated [43]. Therefore, in the future, CPD damage caused by 222-UVC in C. elegans may also be detected in the cell nucleus near the body surface by observing it using the in situ method. ...
Far-ultraviolet radiation C light (far-UVC; 222 nm wavelength) has received attention as a safer light for killing pathogenic bacteria and viruses, as no or little DNA damage is observed after irradiation in mammalian skin models. Far-UVC does not penetrate deeply into tissues; therefore, it cannot reach the underlying critical basal cells. However, it was unclear whether far-UVC (222-UVC) irradiation could cause more biological damage at shallower depths than the 254 nm UVC irradiation (254-UVC), which penetrates more deeply. This study investigated the biological effects of 222- and 254-UVC on the small and transparent model organism Caenorhabditis elegans. At the same energy level of irradiation, 222-UVC introduced slightly less cyclobutane pyrimidine dimer damage to naked DNA in solution than 254-UVC. The survival of eggs laid during 0-4 h after irradiation showed a marked decrease with 254-UVC but not 222-UVC. In addition, defect of chromosomal condensation was observed in a full-grown oocyte by 254-UVC irradiation. In contrast, 222-UVC had a significant effect on the loss of motility of C. elegans. The sensory nervous system, which includes dopamine CEP and PVD neurons on the body surface, was severely damaged by 222-UVC, but not by the same dose of 254-UVC. Interestingly, increasing 254-UVC irradiation by about 10-fold causes similar damage to CEP neurons. These results suggest that 222-UVC is less penetrating, so energy transfer occurs more effectively in tissues near the surface, causing more severe damage than 254-UVC.
... Ptp61F is a Yki/Sd target gene Extended lifespan is often associated with enhanced stress resistance. 53,54 As Ptp61F À/À homozygotes are shorter lived ( Figure 2B), we hypothesized that Ptp61F mutants might have decreased resistance to stress. On the contrary, Ptp61F mutants displayed a significantly increased resistance against paraquat treatment ( Figure S3K). ...
Precise organ size control is fundamental for all metazoans, but how organ size is controlled in a three-dimensional (3D) way remains largely unexplored at the molecular level. Here, we screen and identify Drosophila Ptp61F as a pivotal regulator of organ size that integrates the Hippo pathway, TOR pathway, and actomyosin machinery. Pathologically, Ptp61F loss synergizes with RasV12 to induce tumorigenesis. Physiologically, Ptp61F depletion increases body size and drives neoplastic intestinal tumor formation and stem cell proliferation. Ptp61F also regulates cell contractility and myosin activation and controls 3D cell shape by reducing cell height and horizontal cell size. Mechanistically, Ptp61F forms a complex with Expanded (Ex) and increases endosomal localization of Ex and Yki. Furthermore, we demonstrate that PTPN2, the conserved human ortholog of Ptp61F, can functionally substitute for Ptp61F in Drosophila. Our work defines Ptp61F as an essential determinant that controls 3D organ size under both physiological and pathological conditions.
... To induce mutations and stress, we UV-irradiated Day 2 adults, with a calibrated ultraviolet-C (UV-C) radiation dose of 46 J/m 2 (wavelength 254nm), via 20 s exposure to the UV-C radiation emitted from the lamp of a Thermo Scientific Heraguard ECO Safety Cabinet (calibration details in Supplementary Methods). This dose is in the range of previous UV-C irradiation doses for C. elegans adults or eggs (Meyer et al. 2007;Stergiou et al. 2007;Hyun et al. 2008;Boyd et al. 2010). Our pilot work showed that this dose reduced the fecundity of Day 2 adults laying at 20°C by 61% compared with unexposed sham controls (n = 30 worms/treatment, mean Day 2 offspring count = 35 for UV, 90 for non-UV; full data not shown). ...
... Importantly, we reveal that the absence of a longevity-fecundity trade-off in parents persisted under stressful conditions, when organisms have to invest into repairing UV-induced damage. Previous work in daf-2 mutants has also shown them to be more resistant to UV irradiation (Hyun et al. 2008). ...
Adulthood‐only downregulation of insulin/IGF‐1 signalling (IIS), an evolutionarily conserved pathway regulating resource allocation between somatic maintenance and reproduction, increases lifespan without fecundity cost in the nematode, Caenorhabditis elegans. However, long‐term multigenerational effects of reduced IIS remain unexplored and are proposed to carry costs for offspring quality. To test this hypothesis, we ran a mutation accumulation (MA) experiment and downregulated IIS in half of the 400 MA lines by silencing daf‐2 gene expression using RNA interference (RNAi) across 40 generations. Contrary to the prediction, 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. Reduced IIS increased intergenerational F1 offspring fitness under UV stress but had no quantifiable transgenerational effects. Functional hrde‐1 was required for the benefits of multigenerational daf‐2 RNAi. Overall, we found net benefit to fitness from multigenerational reduction of IIS and the benefits became more apparent under stress. Because reduced daf‐2 expression during development carries fitness costs, we suggest that our findings are best explained by the developmental theory of ageing, which maintains that the decline in the force of selection with age results in poorly regulated gene expression in adulthood. This article is protected by copyright. All rights reserved
... Later, many different factors have been identified to impact aging using C. elegans as a model, including oxidative stress (Larsen, 1993;Vanfleteren, 1993;Park et al., 2009), DNA repair (Hyun et al., 2008;Arczewska et al., 2013;Lans et al., 2013;Fang et al., 2016;SenGupta et al., 2021) and epigenetics (Maures et al., 2011;Li and Casanueva, 2016;Martin-Herranz et al., 2019). Thus, C. elegans is established as a model organism for aging. ...
Since its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.
... The speed of the ageing process may be determined by this rate of accumulation and may be increased by defective DDR mechanisms or by more exposure to genotoxic insults (Nasto et al., 2013). Caenorhabditis elegans mutants with boosted DNA repair capacity exhibit resistance to oxidizing agents and UV radiation, and a longer lifespan than the wild type (Hyun et al., 2008). ...
Background:
DNA damage is a hazard that affects all cells of the body. DNA-damage repair (DDR) mechanisms are in place to repair damage and restore cellular function, as are other damage-induced processes such as apoptosis, autophagy and senescence. The resilience of germ cells and embryos in response to DNA damage is less well studied compared with other cell types. Given that recent studies have described links between embryonic handling techniques and an increased likelihood of disease in post-natal life, an update is needed to summarize the sources of DNA damage in embryos and their capacity to repair it. In addition, numerous recent publications have detailed novel techniques for detecting and repairing DNA damage in embryos. This information is of interest to medical or scientific personnel who wish to obtain undamaged embryos for use in offspring generation by ART.
Objective and rationale:
This review aims to thoroughly discuss sources of DNA damage in male and female gametes and preimplantation embryos. Special consideration is given to current knowledge and limits in DNA damage detection and screening strategies. Finally, obstacles and future perspectives in clinical diagnosis and treatment (repair) of DNA damaged embryos are discussed.
Search methods:
Using PubMed and Google Scholar until May 2021, a comprehensive search for peer-reviewed original English-language articles was carried out using keywords relevant to the topic with no limits placed on time. Keywords included 'DNA damage repair', 'gametes', 'sperm', 'oocyte', 'zygote', 'blastocyst' and 'embryo'. References from retrieved articles were also used to obtain additional articles. Literature on the sources and consequences of DNA damage on germ cells and embryos was also searched. Additional papers cited by primary references were included. Results from our own studies were included where relevant.
Outcomes:
DNA damage in gametes and embryos can differ greatly based on the source and severity. This damage affects the development of the embryo and can lead to long-term health effects on offspring. DDR mechanisms can repair damage to a certain extent, but the factors that play a role in this process are numerous and altogether not well characterized. In this review, we describe the multifactorial origin of DNA damage in male and female gametes and in the embryo, and suggest screening strategies for the selection of healthy gametes and embryos. Furthermore, possible therapeutic solutions to decrease the frequency of DNA damaged gametes and embryos and eventually to repair DNA and increase mitochondrial quality in embryos before their implantation is discussed.
Wider implications:
Understanding DNA damage in gametes and embryos is essential for the improvement of techniques that could enhance embryo implantation and pregnancy success. While our knowledge about DNA damage factors and regulatory mechanisms in cells has advanced greatly, the number of feasible practical techniques to avoid or repair damaged embryos remains scarce. Our intention is therefore to focus on strategies to obtain embryos with as little DNA damage as possible, which will impact reproductive biology research with particular significance for reproductive clinicians and embryologists.
... Also, in humans, the accumulation of DNA damage over time is linked to early ageing [59,60]. Multiple studies suggest that accumulation of unrepaired DNA can gradually reduce cellular functions and accelerate ageing in a variety of species, including Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster [61][62][63][64]. Thus, there is evidence across kingdoms that links DNA damage with early ageing. ...
Ageing in plants is a highly coordinated and complex process that starts with the birth of the plant or plant organ and ends with its death. A vivid manifestation of the final stage of leaf ageing is exemplified by the autumn colours of deciduous trees. Over the past decades, technological advances have allowed plant ageing to be studied on a systems biology level, by means of multi-omics approaches. Here, we review some of these studies and argue that these provide strong support for basic metabolic processes as drivers for ageing. In particular, core cellular processes that control the metabolism of chlorophyll, amino acids, sugars, DNA and reactive oxygen species correlate with leaf ageing. However, while multi-omics studies excel at identifying correlative processes and pathways, molecular genetic approaches can provide proof that such processes and pathways control ageing, by means of knockout and ectopic expression of predicted regulatory genes. Therefore, we also review historic and current molecular evidence to directly test the hypotheses unveiled by the systems biology approaches. We found that the molecular genetic approaches, by and large, confirm the multi-omics-derived hypotheses with notable exceptions, where there is scant evidence that chlorophyll and DNA metabolism are important drivers of leaf ageing. We present a model that summarises the core cellular processes that drive leaf ageing and propose that developmental processes are tightly linked to primary metabolism to inevitably lead to ageing and death.
... Moreover, it results in high levels of intracellular ROS that cause DNA strand breaks, oxidation of DNA bases, and lipid peroxidation [456]. It has been previously shown that daf-2 mutants have a higher DNA repair capacity than the wild type [457]. Here, we wanted to investigate the impact of impairment of de novo fatty acid synthesis on UV stress resistance in daf-2 worms from the aspect of UV irradiation-induced oxidative damage. ...
