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The identification of genes that confer either extension of life span or accelerate age-related decline was a step forward in understanding the mechanisms of aging and revealed that it is partially controlled by genetics and transcriptional programs. Here, we discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C. elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging. [ABSTRACT FROM AUTHOR]

In the context of climate warming, the intensity and frequency of drought occurrences are progressively increasing. However, current research on the impacts of drought on the life-history traits and physiological activities of animals rarely encompasses soil animals that play crucial roles within soil ecosystems. Therefore, this study focused on a soil nematode species (Acrobeloides sp.) and a model nematode (Caenorhabditis elegans) to investigate whether nematodes adjust the trade-off of their life-history traits to confront arid environments, utilizing a Petri dish experiment. Subsequently, we assessed the resilience of the two nematode species to moisture variations by comparing the extent of changes in various indicators (i.e. life-history traits, physiological traits, and oxidative stress) of nematodes before and after drought and rehydration. The results revealed that both nematode species are capable of adapting to arid environments by altering the trade-off between life-history traits. Specifically, they reduce reproductive investment and body mass while maintaining life span, thus responding to drought conditions. Follow-up rehydration experiments post-drought stress highlighted that the soil-dwelling nematode exhibits a superior recovery capacity in response to moisture fluctuations in comparison to the model nematode. To the best of our knowledge, this is the first investigation into life history of drought adaptation within soil-dwelling nematodes. Moreover, the findings hold significant implications for the exploration of drought adaptation and its mechanisms in soil-dwelling animals. [ABSTRACT FROM AUTHOR]

Carica papaya (papaya) leaves has significant nutraceutical properties. However, it is speculated that papaya leaf curl virus (PaLCuV) and papaya ring spot virus (PRSV) can severely affect the therapeutic properties and alter the overall nutraceutical potential of papaya leaves. Therefore, we evaluated the bioactivity of the virus infected papaya leaves extract (PLE) compared to healthy PLE in C. elegans. Viruses infection were confirmed by visual inspection and PCR based detection. Anatomical changes and elemental analysis were analyzed through SEM-EDS. PLE were tested for life span extension and ROS scavenging activity on C. elegans. Infected leaves displayed typical symptoms of curling, distortion and anatomical analysis revealed closed and less number of stomata. Healthy PLE extended (24%) the life span of C. elegans with no significant change in ROS generation while in PaLCuV and PRSV infected PLE, were observed to have significant reduction in the mean life span of 15.4% and 17% with 1.2-fold and 1.9-fold increase in ROS generation. [ABSTRACT FROM AUTHOR]

The food chain can enrich the human body with perchlorate, a novel persistent inorganic contaminant, from the environment. The quantity of perchlorate entering the food chain cannot be ignored, despite the lack of particular facts to support it at the moment. The oxidative stress (ROS, SOD, CAT, MDA, and GSH) in Caenorhabditis elegans was detected in this study using perchlorate as the research object and Caenorhabditis elegans as the model organism. Growth and development-related indicators (body length, life span, and number of eggs laid) of Caenorhabditis elegans exposed to different concentrations of perchlorate were measured, and the associated levels of oxidative stress and growth gene expression were assessed to determine a potential mechanism of perchlorate's influence on Caenorhabditis elegans growth and development. The findings demonstrated that perchlorate dramatically decreased the Caenorhabditis elegans life cycle, spawning frequency, and body length. Additionally, Caenorhabditis elegans had elevated levels of ROS, GSH, and MDA as well as enhanced SOD and CAT activity. Daf-2, Daf--16, Daf--18, Sir-2.1, Skn-1, and other associated genes in the insulin/insulin growth factor signaling pathway may be affected. Through oxidative stress, perchlorate can activate the insulin/insulin growth factor signal pathway and associated genes, affecting growth and development. [ABSTRACT FROM AUTHOR]

The genetic pathways that modulate ageing in multicellular organisms are typically highly conserved across wide evolutionary distances. Recently RNA polymerase III (Pol III) was shown to promote ageing in yeast, C. elegans and D. melanogaster. In this study we investigated the role of Pol III in mammalian ageing using C57BL/6N mice heterozygous for Pol III (Polr3b+/−). We identified sexually dimorphic, organ‐specific beneficial as well as detrimental effects of the Polr3b+/− mutation on health. Female Polr3b+/− mice displayed improved bone health during ageing, but their ability to maintain an effective gut barrier function was compromised and they were susceptible to idiopathic dermatitis (ID). In contrast, male Polr3b+/− mice were lighter than wild‐type (WT) males and had a significantly improved gut barrier function in old age. Several metabolic parameters were affected by both age and sex, but no genotype differences were detected. Neither male nor female Polr3b+/− mice were long‐lived compared to WT controls. Overall, we find no evidence that a reduced Pol III activity extends mouse lifespan but we do find some potential organ‐ and sex‐specific benefits for old‐age health. [ABSTRACT FROM AUTHOR]

Objective: In humans, aging is associated with increased susceptibility to most agerelated diseases. Phloretic acid (PA), a naturally occurring compound found in Ginkgo biloba and Asparagus, exhibits has potential as an anti-aging agent and possesses antioxidant, anti-inflammatory, and immunomodulatory properties. This study aimed to investigate the effects of PA on longevity and stress resistance in Caenorhabditis elegans (C.elegans) and the mechanisms that underlie its effects. Methods: First, we examined the effects of PA on lifespan and healthspan assay, stress resistance and oxidative analysis, lipofuscin levels. Second, we examined the insulin/insulin-like pathway, mitochondria, autophagy-related proteins, and gene expression to explain the possible mechanism of PA prolonging lifespan. Results: Our findings demonstrated that PA dose-dependently extended the C.elegans lifespan, with 200 µM PA showing the greatest effect and increased the C.elegans lifespan by approximately 16.7%. PA enhanced motility and the pharyngeal pumping rate in senescent C.elegans while reducing the accumulation of aging pigments. Further investigations revealed that daf-16, skn-1, and hsf-1 were required for mediating the lifespan extension effect of PA in C.elegans since its impact was suppressed in mutant strains lacking these genes. This suggests that PA activates these genes, leading to the upregulation of downstream genes involved in stress response and senescence regulation pathways. Furthermore, PA did not extend the lifespan of the RNAi atg-18 and RNAi bec-1 but it attenuated SQST-1 accumulation, augmented autophagosome expression, upregulated autophagy-related gene expression, and downregulated S6K protein levels. These findings suggest that the potential life-extending effect of PA also involves the modulation of the autophagy pathway. Conclusion: These findings results highlight the promising anti-aging effects of PA and warrant further investigation into its pharmacological mechanism and medicinal development prospects. [ABSTRACT FROM AUTHOR]

Enterotoxigenic Escherichia coli (ETEC), one of the diarrheagenic E. coli , is the most common cause of diarrhea in developing country and in travelers to those areas. In this study, Caenorhabditis elegans was used as an alternative model host to evaluate ETEC infections. The ETEC strain ETEC1, which was isolated from a patient with diarrhea, possessed enterotoxins STh, LT1, and EAST1 and colonization factors CS2 and CS3. Live ETEC1 shortened the life span and body size of C. elegans in association with increased expression of enterotoxin genes and intestinal colonization. In contrast, heat-killed ETEC1 did not affect the life span of C. elegans. Caenorhabditis elegans infected with ETEC1 showed upregulated expression of genes related to insulin-like peptides and host defense responses. These results suggest that ETEC1 exhibits pathogenicity through intestinal colonization and enterotoxin production in C. elegans. This system is useful as an ETEC infection model. [ABSTRACT FROM AUTHOR]

Sorafenib is a targeted anticancer drug in clinic. Low-dose sorafenib has been reported to activate AMPK through inducing mitochondrial uncoupling without detectable toxicities. AMPK activation has been the approach for extending lifespan, therefore, we investigated the effect of sorafenib on lifespan and physical activity of C. elegans and the underlying mechanisms. In the present study, we found that the effect of sorafenib on C. elegans lifespan was typically hermetic. Sorafenib treatment at higher concentrations (100 μM) was toxic but at lower concentrations (1, 2.5, 5 μM) was beneficial to C. elegans. Sorafenib (1 μM) treatment for whole-life period extended C. elegans lifespan and improved C. elegans physical activity as manifested by increasing pharyngeal pumping and body movement, preserving intestinal barrier integrity, muscle fibers organization and mitochondrial morphology. In addition, sorafenib (1 μM) treatment enhanced C. elegans stress resistance. Sorafenib activated AMPK through inducing mitochondrial uncoupling in C. elegans. Sorafenib treatment activated DAF-16, SKN-1, and increased SOD-3, HSP-16.2, GST-4 expression in C. elegans. Sorafenib treatment induced AMPK-dependent autophagy in C. elegans. We conclude that low-dose sorafenib protects C. elegans against aging through activating AMPK/DAF-16 dependent anti-oxidant pathways and stimulating autophagy responses. Low-dose sorafenib could be a strategy for treating aging and aging-related diseases. [Display omitted] • Sorafenib extends C. elegans lifespan and improves C. elegans physical activity. • Sorafenib treatment enhances stress resistance of C. elegans. • Sorafenib extends C. elegans lifespan via AMPK/DAF-16 dependent anti-oxidant pathways. • Sorafenib induces AMPK-dependent autophagy in C. elegans. [ABSTRACT FROM AUTHOR]

The incidence of age-related neurodegenerative diseases is rising globally. However, the temporal sequence of neurodegeneration throughout adult life is poorly understood. To identify the starting points and schedule of neurodegenerative events, serotonergic and dopaminergic neurons were monitored in the model organism C. elegans, which has a life span of 2–3 weeks. Neural morphology was examined from young to old nematodes that were exposed to silica nanoparticles. Young nematodes showed phenotypes such as dendritic beading of serotonergic and dopaminergic neurons that are normally not seen until late life. During aging, neurodegeneration spreads from specifically susceptible ADF and PDE neurons in young C. elegans to other more resilient neurons, such as dopaminergic CEP in middle-aged worms. Investigation of neurodegenerative hallmarks and animal behavior revealed a temporal correlation with the acceleration of neuromuscular defects, such as internal hatch in 2-day-old C. elegans. Transcriptomics and proteomics of young worms exposed to nano silica showed a change in gene expression concerning the gene ontology groups serotonergic and dopaminergic signaling as well as neuropeptide signaling. Consistent with this, reporter strains for nlp-3, nlp-14 and nlp-21 confirmed premature degeneration of the serotonergic neuron HSN and other neurons in young C. elegans. The results identify young nematodes as a vulnerable age group for nano silica-induced neural defects with a significantly reduced health span. Neurodegeneration of specific neurons impairs signaling by classical neurotransmitters as well as neuropeptides and compromises related neuromuscular behaviors in critical phases of life, such as the reproductive phase. [ABSTRACT FROM AUTHOR]

BACKGROUND: Auricularia polytricha (AP) is traditionally known for its medicinal properties, and linoleic acid (LA) is the prominent component in AP. OBJECTIVE: To understand the anti-aging and stress resistance mechanism induced by AP in Caenorhabditis elegans. METHODS: C. elegans (wild-type (N2), transgenic, and mutant strains) were treated with AP and LA and monitored for lifespan and stress resistance through physiological assays, fluorescence microscopy, and qPCR analysis. Molecular docking studies were employed to identify the interaction mode of LA with DAF-16 and SKN-1. RESULTS: Ethanol extract of AP (APE) was non-toxic and could induce an anti-aging mechanism, as it could extend the lifespan of nematode worms. This was dependent on PMK-1 and DAF-16 as APE could not extend the lifespan of these gene-specific mutants apart from extending the expression of these genes in wild-type nematodes, which was evident from qPCR analysis. LA, too, had a similar effect on the lifespan of wild-type and mutant worms, which further supported the findings. Molecular docking studies pointed to the role of DAF-16 and SKN-1 in regulating the effect of APE. APE also exhibited antioxidant and anti-inflammatory mechanisms as it significantly extended the lifespan in worms exposed to UV-B-induced oxidative stress, thereby showing a protective effect. APE could regulate SKN-1, which was evident from qPCR analysis and the fluorescence of skn-1:GFP transgenic strain. Further qPCR analysis of candidate regulatory genes exhibited antioxidant mechanisms induced by APE. CONCLUSION: APE was observed to induce anti-aging efficacy via SKN-1 and DAF-16. [ABSTRACT FROM AUTHOR]

Although several antidepressants have been identified as potential geroprotectors, the effect and mechanism of fluoxetine, a representative selective serotonin reuptake inhibitor, on longevity have not been fully elucidated. Here, we found that fluoxetine promoted longevity in Caenorhabditis elegans with a concomitant extension of a healthy life span as indicated by increasing mobility, reducing fertility and lipofuscin accumulation, and enhanced resistance to different abiotic stresses. Fluoxetine increased the level of reactive oxygen species (ROS), and antioxidant N-acetylcysteine abolished ROS elevation and the pro-longevity effect of fluoxetine. Additionally, fluoxetine extended life span through the daf-2 - sod-3 pathway in daf-16 -dependent and -independent manners, and fluoxetine-induced life-span extension was abolished in C. elegans sod-3 , daf-2 , and daf-16 mutants. In conclusion, these findings suggest that fluoxetine can promote health and longevity in C. elegans via the interaction of ROS and insulin signaling. [ABSTRACT FROM AUTHOR]

Smilax china L. (Chinaroot) is a natural herb that has multiple uses, such as being used to make tea and food. Both its roots and leaves have different uses due to their unique components. In this study, we analyzed the extract of S. china. roots using LC-HRMS and evaluated the neuroprotective effects and metabolic regulation of S. china on Caenorhabditis elegans. Chinaroot extract prolonged the life span of healthy nematodes, delayed the paralysis time of transgenic CL4176, and reduced the level of β-amyloid deposition in transgenic CL2006. The comprehensive analysis of metabolomics and qRT-PCR revealed that Chinaroot extract exerted neuroprotective effects through the valine, leucine and isoleucine degradation and fatty acid degradation pathways. Moreover, we first discovered that the expressions of T09B4.8, ech-7, and agxt-1 were linked to the neuroprotective effects of Chinaroot. The material exerted neuroprotective effects by modulating metabolic abnormalities in AD model C. elegans. Our study provides a new foundation for the development of functional food properties and functions. [ABSTRACT FROM AUTHOR]

We have shown that multiple tRNA synthetase inhibitors can increase lifespan in both the nematode C. elegans and the budding yeast S. cerevisiae by acting through the conserved transcription factor Gcn4 (yeast)/ATF-4 (worms). To further understand the biology downstream from this conserved transcription factor in the yeast model system, we looked at two different yeast models known to have upregulated Gcn4 and GCN4-dependent increased replicative lifespan. These two models were rpl31aΔ yeast and yeast treated with the tRNA synthetase inhibitor borrelidin. We used both proteomic and RNAseq analysis of a block experimental design that included both of these models to identify GCN4-dependent changes in these two long-lived strains of yeast. Proteomic analysis of these yeast indicate that the long-lived yeast have increased abundances of proteins involved in amino acid biosynthesis. The RNAseq of these same yeast uncovered further regulation of protein degradation, identifying the differential expression of genes associated with autophagy and the ubiquitin–proteasome system (UPS). The data presented here further underscore the important role that GCN4 plays in the maintenance of protein homeostasis, which itself is an important hallmark of aging. In particular, the changes in autophagy and UPS-related gene expression that we have observed could also have wide-ranging implications for the understanding and treatment of diseases of aging that are associated with protein aggregation. [ABSTRACT FROM AUTHOR]

Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer's disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aβ1–42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and "healthspan" (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15–30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality. [ABSTRACT FROM AUTHOR]

Human WIPI β-propellers function as PI3P effectors in autophagy, with WIPI4 and WIPI3 being able to link autophagy control by AMPK and TORC1 to the formation of autophagosomes. WIPI1, instead, assists WIPI2 in efficiently recruiting the ATG16L1 complex at the nascent autophagosome, which in turn promotes lipidation of LC3/GABARAP and autophagosome maturation. However, the specific role of WIPI1 and its regulation are unknown. Here, we discovered the ABL-ERK-MYC signalling axis controlling WIPI1. As a result of this signalling, MYC binds to the WIPI1 promoter and represses WIPI1 gene expression. When ABL-ERK-MYC signalling is counteracted, increased WIPI1 gene expression enhances the formation of autophagic membranes capable of migrating through tunnelling nanotubes to neighbouring cells with low autophagic activity. ABL-regulated WIPI1 function is relevant to lifespan control, as ABL deficiency in C. elegans increased gene expression of the WIPI1 orthologue ATG-18 and prolonged lifespan in a manner dependent on ATG-18. We propose that WIPI1 acts as an enhancer of autophagy that is physiologically relevant for regulating the level of autophagic activity over the lifespan. The ABL-ERK-MYC signaling axis inhibits WIPI1 gene expression, thereby controlling the autophagy-enhancing effect of WIPI1 in the context of C. elegans lifespan control. [ABSTRACT FROM AUTHOR]

Escherichia coli (E. coli) mutant strains have been reported to extend the life span of Caenorhabditis elegans (C. elegans). However, the specific mechanisms through which the genes and pathways affect aging are not yet clear. In this study, we fed Drosophila melanogaster (fruit fly) various E. coli single-gene knockout strains to screen mutant strains with an extended lifespan. The results showed that D. melanogaster fed with E. coli purE had the longest mean lifespan, which was verified by C. elegans. We conducted RNA-sequencing and analysis of C. elegans fed with E. coli purE (a single-gene knockout mutant) to further explore the underlying molecular mechanism. We used differential gene expression (DGE) analysis, enrichment analysis, and gene set enrichment analysis (GSEA) to screen vital genes and modules with significant changes in overall expression. Our results suggest that E. coli mutant strains may affect the host lifespan by regulating the protein synthesis rate (cfz-2) and ATP level (catp-4). To conclude, our study could provide new insights into the genetic influences of the microbiota on the life span of a host and a basis for developing anti-aging probiotics and drugs. [ABSTRACT FROM AUTHOR]

Living longer without simultaneously extending years spent in good health ("health span") is an increasing societal burden, demanding new therapeutic strategies. Hydrogen sulfide (H2S) can correct disease-related mitochondrial metabolic deficiencies, and supraphysiological H2S concentrations can pro health span. However, the efficacy and mechanisms of mitochondrion-targeted sulfide delivery molecules (mtH2S) administered across the adult life course are unknown. Using a Caenorhabditis elegans aging model, we compared untargeted H2S (NaGYY4137, 100 µM and 100 nM) and mtH2S (AP39, 100 nM) donor effects on life span, neuromuscular health span, and mitochondrial integrity. H2S donors were administered from birth or in young/middle-aged animals (day 0, 2, or 4 postadulthood). RNAi pharmacogenetic interventions and transcriptomics/network analysis explored molecular events governing mtH2S donor-mediated health span. Developmentally administered mtH2S (100 nM) improved life/health span vs. equivalent untargeted H2S doses. mtH2S preserved aging mitochondrial structure, content (citrate synthase activity) and neuromuscular strength. Knockdown of H2S metabolism enzymes and FoxO/daf-16 prevented the positive health span effects of mtH2S, whereas DCAF11/wdr-23 - Nrf2/skn-1 oxidative stress protection pathways were dispensable. Health span, but not life span, increased with all adult-onset mtH2S treatments. Adult mtH2S treatment also rejuvenated aging transcriptomes by minimizing expression declines of mitochondria and cytoskeletal components, and peroxisome metabolism hub components, under mechanistic control by the elt-6/elt-3 transcription factor circuit. H2S health span extension likely acts at the mitochondrial level, the mechanisms of which dissociate from life span across adult vs. developmental treatment timings. The small mtH2S doses required for health span extension, combined with efficacy in adult animals, suggest mtH2S is a potential healthy aging therapeutic. [ABSTRACT FROM AUTHOR]

Aging is the root cause of several pathologies like neurological and cardiovascular diseases. Identifying compounds that improve health span and extend life span, called geroprotectors, could be crucial to preventing or at least delaying the onset of age-related diseases. In this regard, the nematode Caenorhabditis elegans (C. elegans) is emerging as an easy, efficient, low-cost model system to screen natural products and identify novel geroprotectors. Phenolic acids can be found in a wide range of natural products that are part of the human diet. Vanillic acid (VA) is a phenolic acid that has previously been attributed with antioxidant, anti-inflammatory, and neuroprotective features. To determine whether these beneficial health effects amount to an extension of health span and life span, in this work, we thoroughly explore the effect of VA on C. elegans stress resistance and life span. We found that VA increases thermotolerance (19.4%), reduces protein aggregation (between 30% and 40%), improves motility, and extends life span by almost 50%, an extent hardly ever achieved with a natural compound. The increased thermotolerance induced by VA is independent of the insulin/insulin-like growth factor-1 signaling pathway but requires heat shock factor-1 and is associated with increased heat shock protein-4 (HSP-4) and hsp-16.2 expression. These results provide new insight into understanding the therapeutical properties of VA and warrant further investigation of VA as a novel geroprotector. [ABSTRACT FROM AUTHOR]

The human life span has been markedly extended since the 1900s, but it has not brought healthy aging to everyone. This increase in life expectancy without an increase in healthspan is a major global concern that imposes considerable health care budgets and degrades the quality of life of older adults. Dietary interventions are a promising strategy to increase healthspan. In this study, we evaluated whether a Gardenia jasminoides Ellis fruit ethanol extract (GFE) increases the life span of Caenorhabditis elegans (C. elegans). Treatment with 10 mg/mL GFE increased the life span by 27.1% when compared to the vehicle group. GFE (10 mg/mL) treatment improved healthspan-related markers (pharyngeal pumping, muscle quality, age–pigment, and reactive oxygen species accumulation) and exerted a protective effect against amyloid β 1–42 toxicity. These effects of GFE are related to the inhibition of insulin/IGF-1 signaling and activation of SKN-1/Nrf, thereby promoting the expression of stress resistance-related genes. In addition, treatment with 10 mM geniposide, the most abundant component of GFE, improved healthspan-related markers and increased life span by 18.55% when compared to the vehicle group. Collectively, these findings demonstrate that GFE and its component geniposide increase the life span along with healthspan in C. elegans. [ABSTRACT FROM AUTHOR]

Curcumin is well known as a potent antioxidant and free radical scavenger and has great potential for anti-aging applications. In this study, we investigate the molecular mechanism of curcumin in prolonging the lifespan of C. elegans. Four concentrations of curcumin (10, 25, 50, and 100 µM) were administered, and the optimal treatment concentration was determined by analyzing the nematode lifespan, physiology, and biochemistry. Additionally, RNA-seq and qRT-PCR were performed to explore the antioxidant effect of curcumin and its underlying mechanism. Results revealed that curcumin could significantly improve the survival capacity of C. elegans without influencing its growth. Curcumin was observed to significantly decrease the levels of reactive oxygen species (ROS) under extreme conditions such as heat stress and paraquat stress. In addition, curcumin increased the amount of nematode mitochondrial DNA (mtDNA) replication. RNA-seq results revealed that the underlying mechanism of curcumin in C. elegans is related to the mitogen-activated protein kinase (MAPK) pathway. qRT-PCR results confirmed that the expression of oxidative stress-related genes (sod-1, sod-2, sod-3, gst-4) was increased, and the expression of MAPK signaling pathway-related genes (sek-1, pmk-1, nsy-1) was significantly downregulated. Furthermore, the administration of curcumin extended the lifespan of nematodes, potentially through the enhancement of oxidative stress resistance and the downregulation of the MAPK signaling pathway. These findings improve our understanding of both lifespan extension and the potential mechanism of curcumin in C. elegans. [ABSTRACT FROM AUTHOR]

RNAi targeting the electron transport chain has been proven to prolong life span in many different species, and experiments specifically with Drosophila melanogaster and Caenorhabditis elegans have shown a distinct role for neurons. To determine which subset of neurons is implicated in this life span extension, we used the GAL4/UAS system to activate RNAi against genes of Complex I and Complex V. We found life span extension of 18–24% with two glutamate neuron (D42 and VGlut) GAL4 lines. We used the GAL80 system to determine if the overlapping set of glutamate neurons in these two GAL4 lines imparts the life span extension. Limiting GAL4 activity to non-VGlut glutamate neurons in the D42 background failed to extend life span, suggesting that glutamate neurons have an important role in aging. Interestingly, RNAi of the electron transport chain in D42 glutamate neurons also caused an increase in daytime and nighttime sleep and a decrease in nighttime locomotor activity. Changes to sleep patterns and prolonged life span were not accompanied by any changes in female fertility or response to starvation. Our findings demonstrate that a small subset of neurons can control life span, and further studies can look into the contributions made by glutamate neurons. [ABSTRACT FROM AUTHOR]

The mechanistic target of rapamycin (mTOR) kinase is one of the top drug targets for promoting health and lifespan extension. Besides rapamycin, only a few other mTOR inhibitors have been developed and shown to be capable of slowing aging. We used machine learning to predict novel small molecules targeting mTOR. We selected one small molecule, TKA001, based on in silico predictions of a high on-target probability, low toxicity, favorable physicochemical properties, and preferable ADMET profile. We modeled TKA001 binding in silico by molecular docking and molecular dynamics. TKA001 potently inhibits both TOR complex 1 and 2 signaling in vitro. Furthermore, TKA001 inhibits human cancer cell proliferation in vitro and extends the lifespan of Caenorhabditis elegans, suggesting that TKA001 is able to slow aging in vivo. [ABSTRACT FROM AUTHOR]

Histone methylation plays crucial roles in the development, gene regulation, and maintenance of stem cell pluripotency in mammals. Recent work shows that histone methylation is associated with aging, yet the underlying mechanism remains unclear. In this work, we identified a class of putative histone 3 lysine 9 mono/dimethyltransferase genes (met-2, set-6, set-19, set-20, set-21, set-32, and set-33), mutations in which induce synergistic lifespan extension in the long-lived DAF-2 (insulin growth factor 1 [IGF-1] receptor) mutant in Caenorhabditis elegans. These putative histone methyltransferase plus daf-2 double mutants not only exhibited an average lifespan nearly three times that of wild-type animals and a maximal lifespan of approximately 100 days, but also significantly increased resistance to oxidative and heat stress. Synergistic lifespan extension depends on the transcription factor DAF-16 (FOXO). mRNA-seq experiments revealed that the mRNA levels of DAF-16 Class I genes, which are activated by DAF-16, were further elevated in the daf-2; set double mutants. Among these genes, tts-1, F35E8.7, ins-35, nhr-62, sod-3, asm-2, and Y39G8B.7 are required for the lifespan extension of the daf-2; set-21 double mutant. In addition, treating daf-2 animals with the H3K9me1/2 methyltransferase G9a inhibitor also extends lifespan and increases stress resistance. Therefore, investigation of DAF-2 and H3K9me1/2 deficiency-mediated synergistic longevity will contribute to a better understanding of the molecular mechanisms of aging and therapeutic applications. [ABSTRACT FROM AUTHOR]

Aging is associated with the increased risk of most age-related diseases in humans. Complanatoside A (CA) is a flavonoid compound isolated from the herbal medicine Semen Astragali Complanati. CA was reported to have potential anti-inflammatory and anti-oxidative activities. In this study, we investigated whether CA could increase the stress resistance capability and life span of Caenorhabditis elegans. Our results showed that CA could extend the longevity of C. elegans in a dosage-dependent manner, while 50 μM of CA has the best effect and increased the life span of C. elegans by about 16.87%. CA also improved the physiological functions in aging worms, such as enhanced locomotor capacity, and reduced the accumulation of the aging pigment. CA could also reduce the accumulation of toxic proteins (α-synuclein and βamyloid) and delay the onset of neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease, in models of C. elegans. Further investigation has revealed that CA requires DAF-16/FOXO, SKN-1, and HSF-1 to extend the life span of C. elegans. CA could increase the antioxidation and detoxification activities regulated by transcription factor SKN-1 and the heat resistance by activating HSF-1 that mediated the expression of the chaperone heat shock proteins. Our results suggest that CA is a potential antiaging agent worth further research for its pharmacological mechanism and development for pharmaceutical applications. [ABSTRACT FROM AUTHOR]

SKN-1, the ortholog of mammalian Nrf2 proteins, is a transcription factor that plays an important role in oxidative stress resistance and longevity. Similar to other defense systems, the Nrf2-mediated stress response is compromised in aging and neurodegenerative diseases. Our previous studies demonstrated that tetramethylpyrazine nitrone (TBN), a derivative of tetramethylpyrazine armed with a potent free radical-scavenging nitrone moiety, exerted multifunctional neuroprotection in neurological and other diseases. However, the ability of TBN to extend a healthy lifespan and its underlying mechanisms of action are not yet clear. C. elegans have become a popular animal model in aging research. Herein, we demonstrate that TBN can extend the lifespan, promote age-associated health indicators, and restore mitochondrial function in C. elegans. TBN also significantly reduced ROS levels and superoxide accumulation in C. elegans. We show that TBN-mediated lifespan extension is SKN-1dependent. The present study provides valuable insights into the mechanisms by which TBN inhibits aging via the Nrf2/SKN-1 pathway in C. elegans. • TBN has significant antioxidative activity in C. elegans. • TBN ameliorates age-related mitochondrial dysfunction in C. elegans. • TBN-mediated lifespan extension of C. elegans by activating the Nrf2. [ABSTRACT FROM AUTHOR]

In aging, physiologic networks decline in function at rates that differ between individuals, producing a wide distribution of lifespan. Though 70% of human lifespan variance remains unexplained by heritable factors, little is known about the intrinsic sources of physiologic heterogeneity in aging. To understand how complex physiologic networks generate lifespan variation, new methods are needed. Here, we present Asynch-seq, an approach that uses gene-expression heterogeneity within isogenic populations to study the processes generating lifespan variation. By collecting thousands of single-individual transcriptomes, we capture the Caenorhabditis elegans "pan-transcriptome"—a highly resolved atlas of non-genetic variation. We use our atlas to guide a large-scale perturbation screen that identifies the decoupling of total mRNA content between germline and soma as the largest source of physiologic heterogeneity in aging, driven by pleiotropic genes whose knockdown dramatically reduces lifespan variance. Our work demonstrates how systematic mapping of physiologic heterogeneity can be applied to reduce inter-individual disparities in aging. [Display omitted] • An atlas of 2,700 individual C. elegans transcriptomes quantifies heterogeneity in aging • A perturbation screen identifies intrinsic drivers of this heterogeneity • Heterogeneity in aging is driven by pleiotropic genes expressed in diverse cell types • Suppressing intrinsic sources of heterogeneity reduces variation in health and lifespan A multi-scale measurement and perturbation approach reveals intrinsic biological sources of inter-individual heterogeneity in gene expression, health, and lifespan. [ABSTRACT FROM AUTHOR]

Methanethiol is a toxic gas produced through bacterial degradation of sulfur‐containing amino acids. Applying a novel enzymatic assay, we here identified a methanethiol oxidase (MTO) that catalyzes the degradation of methanethiol in the nematode Caenorhabditis elegans (C. elegans). The corresponding protein, Y37A1B.5, previously characterized as a C. elegans ortholog of human selenium‐binding protein 1 (SELENBP1), was renamed SEMO‐1 (SELENBP1 ortholog with methanethiol oxidase activity). Worms rendered deficient in SEMO‐1 not only showed decreased hydrogen sulfide production from methanethiol catabolism but they were also more resistant to oxidative stress and had an elevated life span. In contrast, resistance to selenite was significantly lowered in SEMO‐1‐deficient worms. Naturally occurring mutations of human SELENBP1 were introduced to recombinant SEMO‐1 through site‐directed mutagenesis and resulted in loss of its MTO activity, indicating a similar enzymatic mechanism for SELENBP1 and SEMO‐1. In summary, SEMO‐1 confers resistance to toxic selenite and the ability to metabolize toxic methanethiol. These beneficial effects might be a trade‐off for its negative impact on C. elegans life span. [ABSTRACT FROM AUTHOR]

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To explore the role of the small heat shock protein beta 1 (HspB1, also known as Hsp25 in rodents and Hsp27 in humans) in longevity, we created a Caenorhabiditis elegans model with a high level of ubiquitous expression of the naked mole-rat HspB1 protein. The worms showed increased life span under multiple conditions and also increased resistance to heat stress. RNAi experiments suggest that HspB1-induced life extension is dependent on the transcription factors skn-1 (Nrf2) and hsf-1 (Hsf1). RNAseq from HspB1 worms showed an enrichment in several skn-1 target genes, including collagen proteins and lysosomal genes. Expression of HspB1 also improved functional outcomes regulated by SKN-1, specifically oxidative stress resistance and pharyngeal integrity. This work is the first to link a small heat shock protein with collagen function, suggesting a novel role for HspB1 as a hub between canonical heat response signaling and SKN-1 transcription. [ABSTRACT FROM AUTHOR]

Diet regulates complex life‐history traits such as longevity. For optimal lifespan, organisms employ intricate adaptive mechanisms whose molecular underpinnings are less known. We show that Caenorhabditis elegans FLR‐4 kinase prevents lifespan differentials on the bacterial diet having higher Vitamin B12 levels. The flr‐4 mutants are more responsive to the higher B12 levels of Escherichia coli HT115 diet, and consequently, have enhanced flux through the one‐carbon cycle. Mechanistically, a higher level of B12 transcriptionally downregulates the phosphoethanolamine methyltransferase pmt‐2 gene, which modulates phosphatidylcholine (PC) levels. Pmt‐2 downregulation activates cytoprotective gene expression through the p38‐MAPK pathway, leading to increased lifespan only in the mutant. Evidently, preventing bacterial B12 uptake or inhibiting one‐carbon metabolism reverses all the above phenotypes. Conversely, supplementation of B12 to E. coli OP50 or genetically reducing PC levels in the OP50‐fed mutant extends lifespan. Together, we reveal how worms maintain adaptive capacity to diets having varying micronutrient content to ensure a normal lifespan. [ABSTRACT FROM AUTHOR]

Mob1/phocein family proteins are conserved from yeast to mammals. Human has four MOB genes, MOB1, 2, 3 and 4. Human MOB1 protein, which is a component of the Hippo pathway, is involved in the inhibition of yes‐associated protein (YAP1) through large tumor suppressor (LATS) kinases and plays a tumor suppressive role. In contrast, MOB4 activates YAP1. Caernorhabditis elegans (C. elegans) also has four MOB genes. Moreover, C. elegans has homologues of YAP1 (Ce_YAP‐1) and LATS kinases (WTS‐1). Nevertheless, our previous study revealed that the Hippo pathway is not conserved in C. elegans and that heat shock activates Ce_YAP‐1. We also reported that Ce_YAP‐1 is involved in the regulation of life span, healthy lifespan and thermotolerance. In this study, we raised a question whether and how C. elegans homologue of MOB4 (Ce_MOB‐4) is involved in the regulation of Ce_YAP‐1. Ce_MOB‐4 is ubiquitously expressed in adult worms. This expression pattern is similar to that of Ce_YAP‐1. mob‐4 loss‐of‐function mutants show short life span, short health life span and compromise thermotolerance. However, heat shock activates Ce_YAP‐1 in mob‐4 mutant. In conclusion, the role of MOB4 in the activation of YAP1 is not conserved in C. elegans. [ABSTRACT FROM AUTHOR]

The limited heritability of human life spans suggests an important role for gene-environment (G × E) interactions across the life span (T), from gametes to geronts. Multilevel G × E × T interactions of aging phenotypes are conceptualized in the Gero-Exposome as Exogenous and Endogenous domains. Stochastic variations in the Endogenous domain contribute to the diversity of aging phenotypes, shown for the diversity of inbred Caenorhabditis elegans life spans in the same culture environment, and for variegated gene expression of somatic cells in nematodes and mammals. These phenotypic complexities can be analyzed as 3-way interactions of gene, environment, and stochastic variations, the Tripartite Phenotype of Aging. Single-cell analyses provide tools to explore this broadening frontier of biogerontology. [ABSTRACT FROM AUTHOR]

Along with the rapid development of nanotechnology, the biosafety assessment of nanotechnology products, including nanomaterials (NMs), has become more and more important. The nematode Caenorhabditis elegans is a valuable model organism that has been widely used in the field of biology because of its excellent advantages, including low cost, small size, short life span, and highly conservative genomes with vertebral animals. In recent years, the number of nanotoxicological researchers using C. elegans has been growing. According to these available studies, the present review classified the adverse effects of NMs in C. elegans into systematic, cellular, and molecular toxicity, and focused on summarizing and analyzing the underlying mechanisms of metal, metal oxide, and nonmetallic NMs causing toxic effects in C. elegans. Our findings provide insights into what further studies are needed to assess the biosafety of NMs in the ecosystem using C. elegans. Environ Toxicol Chem 2021;40:2406–2424. © 2021 SETAC [ABSTRACT FROM AUTHOR]

Aging and immunity are inextricably linked and many genes that extend life span also enhance immunoresistance. However, it remains unclear whether longevity‐enhancing factors modulate immunity and longevity by discrete or shared mechanisms. Here, we demonstrate that the Caenorhabditis elegans pro‐longevity factor, NHR‐49, also promotes resistance against Pseudomonas aeruginosa but modulates immunity and longevity distinctly. NHR‐49 expression increases upon germline ablation, an intervention that extends life span, but was lowered by Pseudomonas infection. The immunosusceptibility induced by nhr‐49 loss of function was rescued by neuronal NHR‐49 alone, whereas the longevity diminution was rescued by expression in multiple somatic tissues. The well‐established NHR‐49 target genes, acs‐2 and fmo‐2, were also differentially regulated following germline elimination or Pseudomonas exposure. Interestingly, neither gene conferred immunity toward Gram‐negative Pseudomonas, unlike their known functions against gram‐positive pathogens. Instead, genes encoding antimicrobial factors and xenobiotic‐response proteins upregulated by NHR‐49 contributed to resistance against Pseudomonas. Thus, NHR‐49 is differentially regulated by interventions that bring about long‐term changes (life span extension) versus short‐term stress (pathogen exposure) and in response it orchestrates discrete outputs, including pathogen‐specific transcriptional programs. [ABSTRACT FROM AUTHOR]

Perfluorobutane sulfonate (PFBS), due to its increasing use as an alternative to perfluooctane sulfonate (PFOS), is widely detected in humans and the environment, necessitating the evaluation of its potential ecotoxicological risk. We assessed the toxicity and bioaccumulation potential of PFBS in Caenorhabditis elegans, using lethality, locomotion, reproduction, life span, growth, and chemotactic behavior as the effect parameters. In addition, a total of 6 generations of exposed parent animals were monitored for locomotion, brood, and life span behaviors. Life span and brood size were significantly reduced in parent nematodes (P0) following exposure to ≥0.1 mM PFBS, but these negative effects did not transfer to the progeny. Although there was no remarkable effect on reproduction and life span in parent worms exposed to ≤0.01 mM PFBS, multigenerational exposure at 0.0005 mM significantly affected the F4 and F5 progeny. Furthermore, 0.01 to 2.0 mM of PFBS substantially retarded the locomotion behavior of P0 worms. At higher concentrations such as 1.0 mM, this negative effect on locomotion was transferred to the next generation (F1) but later recovered from F2 progeny onward. Our findings demonstrate for the first time that chronic exposure to PFBS at higher concentrations can cause behavioral toxicity and could be transferred to the progeny. These findings have significant implications for the environmental risk assessment of PFBS. Environ Toxicol Chem 2021;40:1973–1982. © 2021 SETAC. [ABSTRACT FROM AUTHOR]

In aging Caenorhabditis elegans, as in higher organisms, there is more than one cause of death. C. elegans exhibit early death with a swollen, infected pharynx (P death), and later death with pharyngeal atrophy (p death). Interventions that alter lifespan can differentially affect frequency and timing of each type of death, generating complex survival curve shapes. Here, we use mortality deconvolution analysis to investigate how reduction of insulin/IGF‐1 signaling (IIS), which increases lifespan (the Age phenotype), affects different forms of death. All daf‐2 insulin/IGF‐1 receptor mutants exhibit increased lifespan in the p subpopulation (p Age), while pleiotropic class 2 daf‐2 mutants show an additional marked reduction in P death frequency. The latter is promoted by pharyngeal expression of the IIS‐regulated DAF‐16 FOXO transcription factor, and at higher temperature by reduced pharyngeal pumping rate. Pharyngeal DAF‐16 also promotes p Age in class 2 daf‐2 mutants, revealing a previously unknown role for the pharynx in the regulation of aging. Necropsy analysis of daf‐2 interactions with the daf‐12 steroid receptor implies that previously described opposing effects of daf‐12 on daf‐2 longevity are attributable to internal hatching of larvae, rather than complex interactions between insulin/IGF‐1 and steroid signaling. These findings support the view that wild‐type IIS acts through multiple distinct mechanisms which promote different life‐limiting pathologies, each of which contribute to late‐life mortality. This study further demonstrates the utility of mortality deconvolution analysis to better understand the genetics of lifespan. [ABSTRACT FROM AUTHOR]

The present study was designed to explore the in vivo -antioxidant capacity and the probable mechanism of AAPs-H, prepared from Auricularia auricula polysaccharides with the optimal extraction conditions by Box–Behnken design and acid hydrolysis, using Caenorhabditis elegans as a model organism. The effects of AAPs-H on the locomotion behavior, life span, antioxidant-related enzymes activities, and antioxidants levels in C. elegans were studied. Furthermore, the potentials of AAPs-H in up-regulating the expression of antioxidant-related genes in C. elegans , such as skn-1 , sod-3 and sir-2.1 , were also discussed. AAPs-H demonstrated a highly significant protective effect against the damage caused by paraquat, could significantly increase U-Turn frequency of worms (p < 0.01), extend their lifespan, enhance antioxidant systems including GR by 63.96% (p < 0.05), GSH-Px by 71.16% (p < 0.01), SOD by 78.65% (p < 0.01) and CAT by 98.52% (p < 0.01), increase the level of GSH by 28.12% (p < 0.05), and decrease the level of MDA by 39.29% (p < 0.01). The qRT-PCR results showed that AAPs-H could up regulate mRNA expression levels of skn-1 , sod-1 , sod-2 , sod-3 and sir-2.1 in wild-type C. elegans (>1.6 fold) when treated with the concentration of 0.4 mg/mL (p < 0.05 or p < 0.01). Our studies provide evidence that AAPs-H improves antioxidant defense system, and up-regulation of oxidative stress related genes for prevention of stress damage in C. elegans. [ABSTRACT FROM AUTHOR]

Portulaca oleracea L. (PO), with abundant natural bioactive phytochemicals, exhibits potential bioactivities and pharmacological activities. However, the mechanisms of action of PO on anti‐aging effect remain unclear. In this study, the ethyl acetate fractional extract from PO (PO‐EA) was obtained by fractionation of solvent extractions, and its effect on lifespan was assessed using the Caenorhabditis elegans (C. elegans). Results showed that PO‐EA could significantly increase the lifespan of C. elegans by 5.31, 12.67, and 16.47% at the doses of 250, 500, and 1,000 µg/mL, respectively. Moreover, PO‐EA significantly promoted the mobility of C. elegans without obvious side effects such as changing body length or decreasing fecundity of the nematodes. Further study demonstrated that PO‐EA could enhance the stress resistance in C. elegans via improving the activities of superoxide dismutase and catalase, and diminishing the contents of reactive oxygen species and malondialdehyde. The gene expression of daf‐12, daf‐16, sod‐3, skn‐1, cat‐1, mev‐1, akt‐1, and sek‐1 were upregulated in C. elegans after administrated by PO‐EA. This study indicated that PO‐EA plays a vital role in extending lifespan and healthspan in C. elegans, and the underlying mechanism of action might be attributed to Insulin/IGF‐1‐like signaling pathways. Therefore, PO‐EA could be served as a potential candidate for anti‐aging functional food. Practical Application: Portulaca oleracea L. (PO) is an edible vegetable that could be used as functional food to exert health benefits for humans such as neuroprotective, antioxidant, anticancer, and anti‐aging effects. Therefore, our findings would provide a strategy to promote the comprehensive utilization of ethyl acetate extract from PO with additional health benefits. [ABSTRACT FROM AUTHOR]

Dietary restriction (DR) increases life span and improves health in most model systems tested, including non-human primates. In C. elegans, as in other models, DR leads to reprogramming of metabolism, improvements in mitochondrial health, large changes in expression of cytoprotective genes and better proteostasis. Understandably, multiple global transcriptional regulators like transcription factors FOXO/DAF-16, FOXA/PHA-4, HSF1/HSF-1 and NRF2/SKN-1 are important for DR longevity. Considering the wide-ranging effects of p53 on organismal biology, we asked whether the C. elegans ortholog, CEP-1 is required for DR-mediated longevity assurance. We employed the widely-used TJ1 strain of cep-1(gk138). We show that cep-1(gk138) suppresses the life span extension of two genetic paradigms of DR, but two non-genetic modes of DR remain unaffected in this strain. We find that two aspects of DR, increased autophagy and up-regulation of the expression of cytoprotective xenobiotic detoxification program (cXDP) genes, are dampened in cep-1(gk138). Importantly, we find that background mutation(s) in the strain may be the actual cause for the phenotypic differences that we observed and cep-1 may not be directly involved in genetic DR-mediated longevity assurance in worms. Identifying these mutation(s) may reveal a novel regulator of longevity required specifically by genetic modes of DR. [ABSTRACT FROM AUTHOR]

• · Toxic effects of beauvericin were analysed in vivo over a broad concentration range using Caenorhabditis elegans • Acute, reproductive and developmental toxicity of beauvericin is moderate. • Low concentrations of beauvericin reduce life span and stress resistance. • Beauvericin increases strongly the number of apoptotic germ cells. • Low concentrations increase lipofuscin accumulation suggesting generation of oxidative stress. Beauvericin is an ubiquitous mycotoxin with relevant occurrence in food and feed. It causes a high toxicity in several cell lines, but its general mechanism of action is not fully understood and only limited in vivo studies have been performed. We used Caenorhabditis elegans as a model organism to investigate effects of beauvericin. The mycotoxin displays a moderate acute toxicity at 100 μM; at this concentration also reproductive toxicity occurred (reduction of total progeny to 32.1 %), developmental toxicity was detectable at 250 μM. However, even lower concentrations were capable to reduce stress resistance and life span of the nematode: A significant reduction was detected at 10 μM beauvericin (decrease in mean survival time of 4.3 % and reduction in life span of 12.9 %). An increase in lipofuscin fluorescence was demonstrated starting at 10 μM suggesting oxidative stress as a mechanism of beauvericin toxicity. Beauvericin (100 μM) increases the number of apoptotic germ cells comparable to the positive control UV-C (400 J/m2). Conclusion: Low concentrations of beauvericin are capable to cause adverse effects in C. elegans , which may be relevant for hazard identification of this compound. [ABSTRACT FROM AUTHOR]

Thermotolerance of an organism is a complex trait that is influenced by a multitude of genetic and environmental factors. Many factors controlling thermotolerance in Caenorhabditis elegans are known to extend life. To understand the regulation of thermotolerance, we performed a genetic screen for mutants with better survival at warm temperature. Here we identified by dauer survival a tax-2 mutation and several mutations disrupting an insulin signaling pathway including the daf-2 gene. While the tax-2 mutant has improved thermotolerance and long life span, the newly identified daf-2 and other insulin signaling mutants, unlike the canonical daf-2(e1370) , do not show improved thermotolerance despite being long-lived. Examination of tax-2 mutations and their mutant phenotypes suggest that the control of thermotolerance is not coupled with the control of life span or dauer survival. With genetic interaction studies, we concluded that tax-2 has complex roles in life span and dauer survival and that tax-2 is a negative regulator of thermotolerance independent of other known thermotolerance genes including those in the insulin signaling pathway. Moreover, cold growth temperature during development weakens the improved thermotolerance associated with tax-2 and other thermotolerance-inducing mutations. Together, this study reveals previously unknown genetic and environmental factors controlling thermotolerance and their complex relationship with life span regulation. [ABSTRACT FROM AUTHOR]

The Caenorhabditis elegans genome possesses homologs of about two-thirds of all human disease genes. Based on its physiological aging characteristics and superiority, the use of C. elegans as a model system for studies on aging, age-related diseases, mechanisms of longevity, and drug screening has been widely acknowledged in recent decades. Lifespan increasing mutations in C. elegans were found to delay aging by impinging several signaling pathways and related epigenetic modifications, including the insulin/IGF-1 signaling (IIS), AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR) pathways. Interestingly, dietary restriction (DR) has been shown to increase the lifespan of numerous metazoans and protect them from multiple age-related pathologies. However, the underlying molecular mechanisms are unclear. In recent decades, C. elegans has been used as a unique model system for high-throughput drug screening. Here, we review C. elegans mutants exhibiting increased in lifespan and age-dependent changes under DR, as well as the utility of C. elegans for drug screening. Thus, we provide evidence for the use of this model organism in research on the prevention of aging. [ABSTRACT FROM AUTHOR]

Aging, a universal and unique process, occurs both intrinsically (chronological) and extrinsically (photoaging). Ultraviolet‐A (UV‐A)‐mediated stress is a growing health hazard to mankind as it is the major cause of photoaging, which could lead to much damage of skin cells and tissues ranging from tan, burn, or even cancer. The present study focuses on the role of antioxidants and other natural compounds which have been widely used in oral/topical applications to combat and delay the effects of photoaging using model nematode Caenorhabditis elegans. Compounds like green tea extract, naringenin, and naringin, which are known for their antioxidant properties, were able to extend life span and healthspan of the nematode in normal as well as under UV‐A‐mediated stress conditions. Regulation of both the stress‐responsive genes (skn‐1 and sir‐2.1) and the aging‐regulating genes (daf‐2 and age‐1) was attributable for these conditions. Interestingly, it was observed that these compounds when combined in equal ratios by weight worked synergistically to combat the aging process. Pronounced synergistic effects were observed during UV‐A‐mediated stress conditions, suggesting that these could be used as potential antiphotoaging compounds which will be of greater significance for health‐based research. [ABSTRACT FROM AUTHOR]

Reduced levels of neural activity are associated with a longer life span in the nematode Caenorhabditis elegans and in mice. Augmented neural activity is associated with a shorter life span. Recent studies show that levels of repressor element 1-silencing transcription factor (REST) increase with normal aging in mice and humans, and reduce neuronal excitation. In C. elegans, increased expression of spr-4, a functional REST homologue, increased the worm life span and is required for classical life span increase mediated by reduced DAF-2/insulin-IGF-1 and increased DAF-16. Preliminary evidence shows that REST and FOXO1, a DAF-16, homologue increase during mammalian aging, and that REST activity is needed for the age-related FOXO1 increase. On the contrary, REST is activated in epilepsy and plays a role in the pathogenesis of Huntington's disease. A simple unifying hypothesis suggests that REST is a "goldilocks-effect factor": too little REST promotes excitotoxic activity, which in turn leads to neurodegenerative diseases such as Alzheimer's. Appropriate increased levels of REST maintain the excitation/inhibition (E-I) balance by reducing potential excitotoxic activity. Increased levels of REST beyond this are toxic as neurons become dysfunctional due to loss of a neuronal phenotype. [ABSTRACT FROM AUTHOR]

[Display omitted] • Tissue-specific overexpression of systemic RNAi components reduces lifespan in C. elegans. • Lifespan reduction interacts with components of systemic RNAi and microRNA pathways. • Bacterial-derived RNAs influence the magnitude of lifespan reduction. • Imbalance between intracellular and extracellular RNAs (InExS) is proposed as a mechanism. • Proper regulation of intertissue RNA signaling is important for longevity. Intertissue RNA transport recently emerged as a novel signaling mechanism. In mammals, mounting evidence suggests that small RNA transfer between cells is widespread and used in various physiological contexts. In the nematode C. elegans , a similar mechanism is conferred by the systemic RNAi pathway. Members of the S ystemic RNA I nterference D efective (SID) family act at different steps of cellular RNA uptake and export. The limiting step in systemic RNA interference (RNAi) is the import of extracellular RNAs via the conserved double-stranded (dsRNA)-gated dsRNA channel SID-1. To better understand the role of RNAs as intertissue signaling molecules, we modified the function of SID-1 in specific tissues of C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in C. elegans intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were attenuated by silencing the components of systemic RNAi sid-1 , sid-2 and sid-5, implicating systemic RNA signaling in the lifespan reduction. Accordingly, tissue-specific overexpression of sid-2 and sid-5 also reduced worm lifespan. Additionally, an RNAi screen for components of several non-coding RNA pathways revealed that silencing the miRNA biogenesis proteins PASH-1 and DCR-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Collectively, our data support the notion that systemic RNA signaling must be tightly regulated, and unbalancing that process provokes a reduction in lifespan. We termed this phenomenon In tercellular/ Ex tracellular S ystemic RNA imbalance (InExS). [ABSTRACT FROM AUTHOR]

This paper addresses how long lifespan can be extended via multiple interventions, such as dietary supplements [e.g., curcumin, resveratrol, sulforaphane, complex phytochemical mixtures (e.g., Moringa, Rhodiola)], pharmaceutical agents (e.g., metformin), caloric restriction, intermittent fasting, exercise and other activities. This evaluation was framed within the context of hormesis, a biphasic dose response with specific quantitative features describing the limits of biological/phenotypic plasticity for integrative biological endpoints (e.g., cell proliferation, memory, fecundity, growth, tissue repair, stem cell population expansion/differentiation, longevity). Evaluation of several hundred lifespan extending agents using yeast, nematode (Caenorhabditis elegans), multiple insect and other invertebrate and vertebrate models (e.g., fish, rodents), revealed they responded in a manner [average (mean/median) and maximum lifespans] consistent with the quantitative features [i.e., 30–60% greater at maximum (Hormesis Rule)] of the hormetic dose response. These lifespan extension features were independent of biological model, inducing agent, endpoints measured and mechanism. These findings indicate that hormesis describes the capacity to extend life via numerous agents and activities and that the magnitude of lifespan extension is modest, in the percentage, not fold, range. These findings have important implications for human aging, genetic diseases/environmental stresses and lifespan extension, as well as public health practices and long-term societal resource planning. [Display omitted] • Hormesis predicts the magnitude of the extent to which lifespan can be extended. • Lifespan extending agents like chemicals, drugs, exercise, fasting were evaluated. • Lifespan extension was independent of biological model, inducing agent, endpoints. • The maximum stimulatory response was 30% to 60% greater than the control group. • Hormesis is therefore a central organizing evolutionary concept. [ABSTRACT FROM AUTHOR]

GABA, a prominent inhibitory neurotransmitter, is best known to regulate neuronal functions in the nervous system. However, much less is known about the role of GABA signaling in other physiological processes. Interestingly, recent work showed that GABA signaling can regulate life span via a metabotropic GABAB receptor in Caenorhabditis elegans. However, the role of other types of GABA receptors in life span has not been clearly defined. It is also unclear whether GABA signaling regulates health span. Here, using C. elegans as a model, we systematically interrogated the role of various GABA receptors in both life span and health span. We find that mutations in four different GABA receptors extend health span by promoting resistance to stress and pathogen infection and that two such receptor mutants also show extended life span. Different GABA receptors engage distinct transcriptional factors to regulate life span and health span, and even the same receptor regulates life span and health span via different transcription factors. Our results uncover a novel, profound role of GABA signaling in aging in C. elegans, which is mediated by different GABA receptors coupled to distinct downstream effectors. [ABSTRACT FROM AUTHOR]

What molecular processes drive cell aging and death? Here, we model how proteostasis--i.e., the folding, chaperoning, and maintenance of protein function--collapses with age from slowed translation and cumulative oxidative damage. Irreparably damaged proteins accumulate with age, increasingly distracting the chaperones from folding the healthy proteins the cell needs. The tipping point to death occurs when replenishing good proteins no longer keeps up with depletion from misfolding, aggregation, and damage. The model agrees with experiments in the worm Caenorhabditis elegans that show the following: Life span shortens nonlinearly with increased temperature or added oxidant concentration, and life span increases in mutants having more chaperones or proteasomes. It predicts observed increases in cellular oxidative damage with age and provides a mechanism for the Gompertz-like rise in mortality observed in humans and other organisms. Overall, the model shows how the instability of proteins sets the rate at which damage accumulates with age and upends a cell's normal proteostasis balance. [ABSTRACT FROM AUTHOR]

Unfolded protein response (UPR) of the endoplasmic reticulum (UPRER) helps maintain proteostasis in the cell. The ability to mount an effective UPRER to external stress (iUPRER) decreases with age and is linked to the pathophysiology of multiple agerelated disorders. Here, we show that a transient pharmacological ER stress, imposed early in development on Caenorhabditis elegans, enhances proteostasis, prevents iUPRER decline with age, and increases adult life span. Importantly, dietary restriction (DR), that has a conserved positive effect on life span, employs this mechanism of ER hormesis for longevity assurance. We found that only the IRE-1-XBP-1 branch of UPRER is required for the longevity effects, resulting in increased ER-associated degradation (ERAD) gene expression and degradation of ER resident proteins during DR. Further, both ER hormesis and DR protect against polyglutamine aggregation in an IRE-1-dependent manner. We show that the DR-specific FOXA transcription factor PHA-4 transcriptionally regulates the genes required for ER homeostasis and is required for ER preconditioning-induced life span extension. Finally, we show that ER hormesis improves proteostasis and viability in a mammalian cellular model of neurodegenerative disease. Together, our study identifies a mechanism by which DR offers its benefits and opens the possibility of using ER-targeted pharmacological interventions to mimic the prolongevity effects of DR. [ABSTRACT FROM AUTHOR]