Bacterium-induced internal egg hatching frequency is predictive of life span in Caenorhabditis elegans populations.
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ABSTRACT:
SUBMITTER: Mosser T
PROVIDER: S-EPMC3208991 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The identification and characterization of age-related degenerative changes is a critical goal because it can elucidate mechanisms of aging biology and contribute to understanding interventions that promote longevity. Here, we document a novel, age-related degenerative change in C. elegans hermaphrodites, an important model system for the genetic analysis of longevity. Matricidal hatching--intra-uterine hatching of progeny that causes maternal death--displayed an age-related increase in frequency and affected ~70% of mated, wild-type hermaphrodites. The timing and incidence of matricidal hatching were largely independent of the levels of early and total progeny production and the duration of male exposure. Thus, matricidal hatching appears to reflect intrinsic age-related degeneration of the egg-laying system rather than use-dependent damage accumulation. Consistent with this model, mutations that extend longevity by causing dietary restriction significantly delayed matricidal hatching, indicating age-related degeneration of the egg-laying system is controlled by nutrient availability. To identify the underlying tissue defect, we analyzed serotonin signaling that triggers vulval muscle contractions. Mated hermaphrodites displayed an age-related decline in the ability to lay eggs in response to exogenous serotonin, indicating that vulval muscles and/or a further downstream function that is necessary for egg laying degenerate in an age-related manner. By characterizing a new, age-related degenerative event displayed by C. elegans hermaphrodites, these studies contribute to understanding a frequent cause of death in mated hermaphrodites and establish a model of age-related reproductive complications that may be relevant to the birthing process in other animals such as humans.
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Project description:In the present study, we tested the antioxidant activity of phycoerythrin (PE, an oligomeric light harvesting protein isolated from Lyngbya sp. A09DM) to curtail aging effects in Caenorhabditis elegans. Purified PE (100 ?g/ml) dietary supplement was given to C. elegans and investigated for its anti-aging potential. PE treatment improved the mean life span of wild type (N2)-animals from 15?±?0.1 to 19.9?±?0.3 days. PE treatment also moderated the decline in aging-associated physiological functions like pharyngeal pumping and locomotion with increasing age of N2 worms. Moreover, PE treatment also enhanced the stress tolerance in 5-day-aged adults with increase in mean survival rate from 22.2?±?2.5 to 41.6?±?2.5% under thermo stress and from 30.1?±?3.2 to 63.1?±?6.4% under oxidative (hydrogen peroxide)-stress. PE treatment was also noted to moderate the heat-induced expression of human amyloid-beta(A?1-42) peptide and associated paralysis in the muscle tissues of transgenic C. elegans CL4176 (Alzheimer's disease model). Effectiveness of PE in expanding the life span of mutant C. elegans, knockout for some up (daf-2 and age-1)- and down (daf-16)-stream regulators of insulin/IGF-1 signaling (IIS), shows the independency of PE effect from DAF-2-AGE-1-DAF-16 signaling pathway. Moreover, the inability of PE in expanding the life span of hsf-1 knockout C. elegans(sy441) suggests the dependency of PE effect on heat shock transcription factor (HSF-1) controlling stress-induced gene expression. In conclusion, our results demonstrated a novel anti-aging activity of PE which conferred increased resistance to cellular stress resulting in improved life span and health span of C. elegans.
| S-EPMC4199339 | biostudies-literature
Project description:Animal aging is characterized by progressive, degenerative changes in many organ systems. Because age-related degeneration is a major contributor to disability and death in humans, treatments that delay age-related degeneration are desirable. However, no drugs that delay normal human aging are currently available. To identify drugs that delay age-related degeneration, we used the powerful Caenorhabditis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan. To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.
| S-EPMC4769152 | biostudies-literature
Project description:Little is known regarding how the synthesis and degradation of individual proteins change during the life of an organism. Such knowledge is vital to understanding the aging process. To fill this knowledge gap, we monitored newly synthesized proteins on a proteome scale in Caenorhabditis elegans over time during adulthood using a stable-isotope labeling by amino acids in cell culture (SILAC)-based label-chase approach. For most proteins, the rate of appearance of newly synthesized protein was high during the first 5 days of adulthood, slowed down between the fifth and the 11th days, and then increased again after the 11th day. However, the magnitude of appearance rate differed significantly from protein to protein. For example, the appearance of newly synthesized protein was fast for proteins involved in embryonic development, transcription regulation, and lipid binding/transport, with >70% of these proteins newly synthesized by day 5 of adulthood, whereas it was slow for proteins involved in cellular assembly and motility, such as actin and myosin, with <70% of these proteins newly synthesized even on day 16. The late-life increase of newly synthesized protein was especially high for ribosomal proteins and ATP synthases. We also investigated the effect of RNAi-mediated knockdown of the rpl-9 (ribosomal protein), atp-3 (ATP synthase), and ril-1 (RNAi-induced longevity-1) genes and found that inhibiting the expression of atp-3 and ril-1 beginning in late adulthood is still effective to extend the life span of C. elegans.
| S-EPMC4440835 | biostudies-literature
Project description:Aging is a complex phenotype responsive to a plethora of environmental inputs; yet only a limited number of transcriptional regulators are known to influence life span. How the downstream expression programs mediated by these factors (or others) are coordinated into common or distinct set of aging effectors is an addressable question in model organisms, such as C. elegans. Here, we establish the transcription factor ETS-4, an ortholog of vertebrate SPDEF, as a longevity determinant. Adult worms with ets-4 mutations had a significant extension of mean life span. Restoring ETS-4 activity in the intestine, but not neurons, of ets-4 mutant worms rescued life span to wild-type levels. Using RNAi, we demonstrated that ets-4 is required post-developmentally to regulate adult life span; thus uncoupling the role of ETS-4 in aging from potential functions in worm intestinal development. Seventy ETS-4-regulated genes, identified by gene expression profiling of two distinct ets-4 alleles and analyzed by bioinformatics, were enriched for known longevity effectors that function in lipid transport, lipid metabolism, and innate immunity. Putative target genes were enriched for ones that change expression during normal aging, the majority of which are controlled by the GATA factors. Also, some ETS-4-regulated genes function downstream of the FOXO factor, DAF-16 and the insulin/IGF-1 signaling pathway. However, epistasis and phenotypic analyses indicate that ets-4 functioned in parallel to the insulin/IGF-1 receptor, daf-2 and akt-1/2 kinases. Furthermore, ets-4 required daf-16 to modulate aging, suggesting overlap in function at the level of common targets that affect life span. In conclusion, ETS-4 is a new transcriptional regulator of aging, which shares transcriptional targets with GATA and FOXO factors, suggesting that overlapping pathways direct common sets of lifespan-related genes.
| S-EPMC2940738 | biostudies-literature
Project description:Genetically identical organisms grown in homogenous environments differ in quantitative phenotypes. Differences in one such trait, expression of a single biomarker gene, can identify isogenic cells or organisms that later manifest different fates. For example, in isogenic populations of young adult Caenorhabditis elegans, differences in Green Fluorescent Protein (GFP) expressed from the hsp-16.2 promoter predict differences in life span. Thus, it is of interest to determine how interindividual differences in biomarker gene expression arise. Prior reports showed that the thermosensory neurons and insulin signaling systems controlled the magnitude of the heat shock response, including absolute expression of hsp-16.2. Here, we tested whether these regulatory signals might also influence variation in hsp-16.2 reporter expression. Genetic experiments showed that the action of AFD thermosensory neurons increases interindividual variation in biomarker expression. Further genetic experimentation showed the insulin signaling system acts to decrease interindividual variation in life-span biomarker expression; in other words, insulin signaling canalizes expression of the hsp-16.2-driven life-span biomarker. Our results show that specific signaling systems regulate not only expression level, but also the amount of interindividual expression variation for a life-span biomarker gene. They raise the possibility that manipulation of these systems might offer means to reduce heterogeneity in the aging process.
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Project description:Animals, particularly poikilotherms, exhibit distinct physiologies at different environmental temperatures. Here, we hypothesized that temperature-based differences in physiology could affect the amount of variation in complex quantitative traits. Specifically, we examined, in Caenorhabditis elegans, how different temperatures (15°C, 20°C, and 25°C) affected the amount of interindividual variation in life span and also expression of three reporter genes-transcriptional reporters for vit-2, gpd-2, and hsp-16.2 (a life-span biomarker). We found the expected inverse relationship between temperature and average life span. Surprisingly, we found that at the highest temperature, there were fewer differences between individuals in life span and less interindividual variation in expression of all three reporters. We suggest that growth at 25°C might canalize (reduce interindividual differences in) life span and expression of some genes by eliciting a small constitutive heat shock response. Growth at 25°C requires wild-type hsf-1, which encodes the main heat shock response transcriptional activator. We speculate that increased chaperone activity at 25°C may reduce interindividual variation in gene expression by increasing protein folding efficiency. We hypothesize that reduced variation in gene expression may ultimately cause reduced variation in life span.
| S-EPMC5861850 | biostudies-other
Project description:Genetic changes resulting in increased life span are often positively associated with enhanced stress resistance and somatic maintenance. A recent study found that certain long-lived Caenorhabditis elegans mutants spent a decreased proportion of total life in a healthy state compared with controls, raising concerns about how the relationship between health and longevity is assessed. We evaluated seven markers of health and two health-span models for their suitability in assessing age-associated health in invertebrates using C elegans strains not expected to outperform wild-type animals. Additionally, we used an empirical method to determine the transition point into failing health based on the greatest rate of change with age for each marker. As expected, animals with mutations causing sickness or accelerated aging had reduced health span when compared chronologically to wild-type animals. Physiological health span, the proportion of total life spent healthy, was reduced for locomotion markers in chronically ill mutants, but, surprisingly, was extended for thermotolerance. In contrast, all short-lived mutants had reduced "quality-of-life" in another model recently employed for assessing invertebrate health. Results suggest that the interpretation of physiological health span is not straightforward, possibly because it factors out time and thus does not account for the added cost of extrinsic forces on longer-lived strains.
| S-EPMC6075462 | biostudies-other
Project description:The scorpion has been extensively used in various pharmacological profiles or as food supplies. The exploration of scorpion venom has been reported due to the presence of recombinant peptides. rBm?TX14 is an ?-neurotoxin extracted from the venom gland of the East Asian scorpion Buthus martensii Karsch and can affect ion channel conductance. Here, we investigated the functions of rBm?TX14 using the Caenorhabditis elegans model. Using western blot analysis, rBm?TX14 was shown to be expressed both in the cytoplasm and inclusion bodies in the E.coli Rosetta (DE3) strain. Circular dichroism spectroscopy analysis demonstrated that purified rBm?TX14 retained its biological structures. Next, feeding nematodes with E.coli Rosetta (DE3) expressing rBm?TX14 caused extension of the life span and promoted the locomotion of the nematodes. In addition, we identified several genes that play various roles in the life span and locomotion of C. elegans through microarray analysis and quantitative real-time PCR. Furthermore, if the amino acid site H15 of rBm?TX14 was mutated, rBm?TX14 no longer promoted the C. elegans life span. In conclusion, the results not only demonstrated the functions and mechanism of rBm?TX14 in C. elegans, but also provided the new sight in the utility of recombinant peptides from scorpion venom.
| S-EPMC5017660 | biostudies-literature
Project description:Transactive response DNA-binding protein (TARDBP/TDP-43), a heterogeneous nuclear ribonucleoprotein (hnRNP) with diverse activities, is a common denominator in several neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Orthologs of TDP-43 exist in animals ranging from mammals to invertebrates. Here, we systematically studied mutant Caenorhabditis elegans lacking the nematode TDP-43 ortholog, TDP-1. Heterologous expression of human TDP-43 rescued the defects in C. elegans lacking TDP-1, suggesting their functions are conserved. Although the tdp-1 mutants exhibited deficits in fertility, growth, and locomotion, loss of tdp-1 attenuated defects in several C. elegans models of proteotoxicity. Loss of tdp-1 suppressed defects in transgenic C. elegans expressing TDP-43 or CuZn superoxide dismutase, both of which are associated with proteotoxicity in neurodegenerative diseases. Loss of tdp-1 also reduced defects in mutant animals lacking the heat shock factor HSF-1. Transcriptional profiling demonstrated that the loss of TDP-1 altered expression of genes functioning in RNA processing and protein folding. Furthermore, the absence of tdp-1 extended the life span in C. elegans. The life span extension required a FOXO transcriptional factor DAF-16 but not HSF-1. These results suggest that the C. elegans TDP-1 has a role in the regulation of protein homeostasis and aging.
| S-EPMC3318719 | biostudies-literature