Aging In Caenorhabditis Elegans Research Articles

Differential impacts of nonsteroidal anti-inflammatory drugs on lifespan and healthspan in aged Caenorhabditis elegans.

Aging and age-related diseases are intricately associated with oxidative stress and inflammation. Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown their promise in mitigating age-related conditions and potentially extending lifespan in various model organisms. However, the efficacy of NSAIDs in older individuals may be influenced by age-related changes in drug metabolism and tolerance, which could result in age-dependent toxicities. This study aimed to evaluate the potential risks of toxicities associated with commonly used NSAIDs (aspirin, ibuprofen, acetaminophen, and indomethacin) on lifespan, healthspan, and oxidative stress levels in both young and old Caenorhabditis elegans. The results revealed that aspirin and ibuprofen were able to extend lifespan in both young and old worms by suppressing ROS generation and enhancing the expression of antioxidant SOD genes. In contrast, acetaminophen and indomeacin accelerated aging process in old worms, leading to oxidative stress damage and reduced resistance to heat stress through the pmk-1/skn-1 pathway. Notably, the harmful effects of acetaminophen and indomeacin were mitigated when pmk-1 was knocked out in the pmk-1(km25) strain. These results underscore the potential lack of benefit from acetaminophen and indomeacin in elderly individuals due to their increased susceptibility to toxicity. Further research is essential to elucidate the underlying mechanisms driving these age-dependent responses and to evaluate the potential risks associated with NSAID use in the elderly population.

RSU-1 regulates the integrity of dense bodies in muscle cells of aging Caenorhabditis elegans

RSU-1 regulates the integrity of dense bodies in muscle cells of aging Caenorhabditis elegans

Decoding lifespan secrets: the role of the gonad in Caenorhabditis elegans aging.

The gonad has become a central organ for understanding aging in C. elegans, as removing the proliferating stem cells in the germline results in significant lifespan extension. Similarly, when starvation in late larval stages leads to the quiescence of germline stem cells the adult nematode enters reproductive diapause, associated with an extended lifespan. This review summarizes recent advancements in identifying the mechanisms behind gonad-mediated lifespan extension, including comparisons with other nematodes and the role of lipid signaling and transcriptional changes. Given that the gonad also mediates lifespan regulation in other invertebrates and vertebrates, elucidating the underlying mechanisms may help to gain new insights into the mechanisms and evolution of aging.

Considering Caenorhabditis elegans Aging on a Temporal and Tissue Scale: The Case of Insulin/IGF-1 Signaling.

The aging process is inherently complex, involving multiple mechanisms that interact at different biological scales. The nematode Caenorhabditis elegans is a simple model organism that has played a pivotal role in aging research following the discovery of mutations extending lifespan. Longevity pathways identified in C. elegans were subsequently found to be conserved and regulate lifespan in multiple species. These pathways intersect with fundamental hallmarks of aging that include nutrient sensing, epigenetic alterations, proteostasis loss, and mitochondrial dysfunction. Here we summarize recent data obtained in C. elegans highlighting the importance of studying aging at both the tissue and temporal scale. We then focus on the neuromuscular system to illustrate the kinetics of changes that take place with age. We describe recently developed tools that enabled the dissection of the contribution of the insulin/IGF-1 receptor ortholog DAF-2 to the regulation of worm mobility in specific tissues and at different ages. We also discuss guidelines and potential pitfalls in the use of these new tools. We further highlight the opportunities that they present, especially when combined with recent transcriptomic data, to address and resolve the inherent complexity of aging. Understanding how different aging processes interact within and between tissues at different life stages could ultimately suggest potential intervention points for age-related diseases.

On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging

Tryptophan metabolism through the kynurenine pathway influences molecular processes critical to healthy aging including immune signaling, redox homeostasis, and energy production. Aberrant kynurenine metabolism occurs during normal aging and is implicated in many age-associated pathologies including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. We and others previously identified three kynurenine pathway genes—tdo-2, kynu-1, and acsd-1—for which decreasing expression extends lifespan in invertebrates. Here we report that knockdown of haao-1, a fourth gene encoding the enzyme 3-hydroxyanthranilic acid (3HAA) dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated health decline in Caenorhabditis elegans. Lifespan extension is mediated by increased physiological levels of the HAAO substrate 3HAA. 3HAA increases oxidative stress resistance and activates the Nrf2/SKN-1 oxidative stress response. In pilot studies, female Haao knockout mice or aging wild type male mice fed 3HAA supplemented diet were also long-lived. HAAO and 3HAA represent potential therapeutic targets for aging and age-associated disease.

Handelin alleviates cachexia- and aging-induced skeletal muscle atrophy by improving protein homeostasis and inhibiting inflammation.

Handelin is a bioactive compound from Chrysanthemum indicum L. that improves motor function and muscle integrity during aging in Caenorhabditis elegans. This study aimed to further evaluate the protective effects and molecular mechanisms of handelin in a mouse muscle atrophy model induced by cachexia and aging. A tumour necrosis factor (TNF)-α-induced atrophy model was used to examine handelin activity in cultured C2C12 myotubes in vitro. Lipopolysaccharide (LPS)-treated 8-week-old model mice and 23-month-old (aged) mice were used to examine the therapeutic effects of handelin on cachexia- and aging-induced muscle atrophy, respectively, in vivo. Protein and mRNA expressions were analysed by Western blotting, ELISA and quantitative PCR, respectively. Skeletal muscle mass was measured by histological analysis. Handelin treatment resulted in an upregulation of protein levels of early (MyoD and myogenin) and late (myosin heavy chain, MyHC) differentiation markers in C2C12 myotubes (P<0.05), and enhanced mitochondrial respiratory (P<0.05). In TNF-α-induced myotube atrophy model, handelin maintained MyHC protein levels, increased insulin-like growth factor (Igf1) mRNA expression and phosphorylated protein kinase B protein levels (P<0.05). Handelin also reduced atrogin-1 expression, inhibited nuclear factor-κB activation and reduced mRNA levels of interleukin (Il)6, Il1b and chemokine ligand 1 (Cxcl1) (P<0.05). In LPS-treated mice, handelin increased body weight (P<0.05), the weight (P<0.01) and cross-sectional area (CSA) of the soleus muscle (P<0.0001) and improved motor function (P<0.05). In aged mice, handelin slightly increased the weight of the tibialis anterior muscle (P=0.06) and CSA of the tibialis anterior and gastrocnemius muscles (P<0.0001). In the tibialis anterior muscle of aged mice, handelin upregulated mRNA levels of Igf1 (P<0.01), anti-inflammatory cytokine Il10 (P<0.01), mitochondrial biogenesis genes (P<0.05) and antioxidant-related enzymes (P<0.05) and strengthened Sod and Cat enzyme activity (P<0.05). Handelin also reduced lipid peroxidation and protein carbonylation, downregulated mRNA levels of Fbxo32, Mstn, Cxcl1, Il1b and Tnf (P<0.05), and decreased IL-1β levels in serum (P<0.05). Knockdown of Hsp70 or using an Hsp70 inhibitor abolished the ameliorating effects of handelin on myotube atrophy. Handelin ameliorated cachexia- and aging-induced skeletal muscle atrophy in vitro and in vivo, by maintaining homeostasis of protein synthesis and degradation, possibly by inhibiting inflammation. Handelin is a potentially promising drug candidate for the treatment of muscle wasting.

Microbes are potential key players in the evolution of life histories and aging in Caenorhabditis elegans.

Microbes can have profound effects on host fitness and health and the appearance of late-onset diseases. Host-microbe interactions thus represent a major environmental context for healthy aging of the host and might also mediate trade-offs between life-history traits in the evolution of host senescence. Here, we have used the nematode Caenorhabditis elegans to study how host-microbe interactions may modulate the evolution of life histories and aging. We first characterized the effects of two non-pathogenic and one pathogenic Escherichia coli strains, together with the pathogenic Serratia marcescens DB11 strain, on population growth rates and survival of C. elegans from five different genetic backgrounds. We then focused on an outbred C. elegans population, to understand if microbe-specific effects on the reproductive schedule and in traits such as developmental rate and survival were also expressed in the presence of males and standing genetic variation, which could be relevant for the evolution of C. elegans and other nematode species in nature. Our results show that host-microbe interactions have a substantial host-genotype-dependent impact on the reproductive aging and survival of the nematode host. Although both pathogenic bacteria reduced host survival in comparison with benign strains, they differed in how they affected other host traits. Host fertility and population growth rate were affected by S. marcescens DB11 only during early adulthood, whereas this occurred at later ages with the pathogenic E. coli IAI1. In both cases, these effects were largely dependent on the host genotypes. Given such microbe-specific genotypic differences in host life history, we predict that the evolution of reproductive schedules and senescence might be critically contingent on host-microbe interactions in nature.

Nuclear hormone receptor NHR-49 is an essential regulator of stress resilience and healthy aging in Caenorhabditis elegans.

The genome of Caenorhabditis elegans encodes 284 nuclear hormone receptor, which perform diverse functions in development and physiology. One of the best characterized of these is NHR-49, related in sequence and function to mammalian hepatocyte nuclear factor 4α and peroxisome proliferator-activated receptor α. Initially identified as regulator of lipid metabolism, including fatty acid catabolism and desaturation, additional important roles for NHR-49 have since emerged. It is an essential contributor to longevity in several genetic and environmental contexts, and also plays vital roles in the resistance to several stresses and innate immune response to infection with various bacterial pathogens. Here, we review how NHR-49 is integrated into pertinent signaling circuits and how it achieves its diverse functions. We also highlight areas for future investigation including identification of regulatory inputs that drive NHR-49 activity and identification of tissue-specific gene regulatory outputs. We anticipate that future work on this protein will provide information that could be useful for developing strategies to age-associated declines in health and age-related human diseases.

Individual cell types in C. elegans age differently and activate distinct cell-protective responses

Aging is characterized by a global decline in physiological function. However, by constructing a complete single-cell gene expression atlas, we find that Caenorhabditis elegans aging is not random in nature but instead is characterized by coordinated changes in functionally related metabolic, proteostasis, and stress-response genes in a cell-type-specific fashion, with downregulation of energy metabolism being the only nearly universal change. Similarly, the rates at which cells age differ significantly between cell types. In some cell types, aging is characterized by an increase in cell-to-cell variance, whereas in others, variance actually decreases. Remarkably, multiple resilience-enhancing transcription factors known to extend lifespan are activated across many cell types with age; we discovered new longevity candidates, such as GEI-3, among these. Together, our findings suggest that cells do not age passively but instead react strongly, and individualistically, to events that occur during aging. This atlas can be queried through a public interface.

Mitochondrial sulfide promotes life span and health span through distinct mechanisms in developing versus adult treated Caenorhabditis elegans

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.

Homeodomain-interacting protein kinase maintains neuronal homeostasis during normal Caenorhabditis elegans aging and systemically regulates longevity from serotonergic and GABAergic neurons.

Aging and the age-associated decline of the proteome is determined in part through neuronal control of evolutionarily conserved transcriptional effectors, which safeguard homeostasis under fluctuating metabolic and stress conditions by regulating an expansive proteostatic network. We have discovered the Caenorhabditis elegans homeodomain-interacting protein kinase (HPK-1) acts as a key transcriptional effector to preserve neuronal integrity, function, and proteostasis during aging. Loss of hpk-1 results in drastic dysregulation in expression of neuronal genes, including genes associated with neuronal aging. During normal aging hpk-1 expression increases throughout the nervous system more broadly than any other kinase. Within the aging nervous system, hpk-1 induction overlaps with key longevity transcription factors, which suggests hpk-1 expression mitigates natural age-associated physiological decline. Consistently, pan-neuronal overexpression of hpk-1 extends longevity, preserves proteostasis both within and outside of the nervous system, and improves stress resistance. Neuronal HPK-1 improves proteostasis through kinase activity. HPK-1 functions cell non-autonomously within serotonergic and GABAergic neurons to improve proteostasis in distal tissues by specifically regulating distinct components of the proteostatic network. Increased serotonergic HPK-1 enhances the heat shock response and survival to acute stress. In contrast, GABAergic HPK-1 induces basal autophagy and extends longevity, which requires mxl-2 (MLX), hlh-30 (TFEB), and daf-16 (FOXO). Our work establishes hpk-1 as a key neuronal transcriptional regulator critical for preservation of neuronal function during aging. Further, these data provide novel insight as to how the nervous system partitions acute and chronic adaptive response pathways to delay aging by maintaining organismal homeostasis.

Identifying lipid particle sub-types in live Caenorhabditis elegans with two-photon fluorescence lifetime imaging.

Fat metabolism is an important modifier of aging and longevity in Caenorhabditis elegans. Given the anatomy and hermaphroditic nature of C. elegans, a major challenge is to distinguish fats that serve the energetic needs of the parent from those that are allocated to the progeny. Broadband coherent anti-Stokes Raman scattering (BCARS) microscopy has revealed that the composition and dynamics of lipid particles are heterogeneous both within and between different tissues of this organism. Using BCARS, we have previously succeeded in distinguishing lipid-rich particles that serve as energetic reservoirs of the parent from those that are destined for the progeny. While BCARS microscopy produces high-resolution images with very high information content, it is not yet a widely available platform. Here we report a new approach combining the lipophilic vital dye Nile Red and two-photon fluorescence lifetime imaging microscopy (2p-FLIM) for the in vivo discrimination of lipid particle sub-types. While it is widely accepted that Nile Red staining yields unreliable results for detecting lipid structures in live C. elegans due to strong interference of autofluorescence and non-specific staining signals, our results show that simple FLIM phasor analysis can effectively separate those signals and is capable of differentiating the non-polar lipid-dominant (lipid-storage), polar lipid-dominant (yolk lipoprotein) particles, and the intermediates that have been observed using BCARS microscopy. An advantage of this approach is that images can be acquired using common, commercially available 2p-FLIM systems within about 10% of the time required to generate a BCARS image. Our work provides a novel, broadly accessible approach for analyzing lipid-containing structures in a complex, live whole organism context.

Mitochondria hormesis delays aging and associated diseases in Caenorhabditis elegans impacting on key ferroptosis players.

Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode Caenorhabditis elegans. Instead, sub-lethal iron depletion extends C.elegans lifespan. Hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage across species but it has low feasible application. In this study, we assessed the potential beneficial effects of genetic and chemical interventions acting via mild iron instead of oxygen depletion. We show that limiting iron availability in C. elegans through frataxin silencing or the iron chelator bipyridine, similar to hypoxia preconditioning, protects against hypoxia-, age-, and proteotoxicity-induced neuromuscular deficits. Mechanistically, our data suggest that the beneficial effects elicited by frataxin silencing are in part mediated by counteracting ferroptosis, a form of non-apoptotic cell death mediated by iron-induced lipid peroxidation. This is achieved by impacting on different key ferroptosis players and likely via gpx-independent redox systems. We thus point to ferroptosis inhibition as a novel potential strategy to promote healthy aging.

The Attenuation of Insulin/IGF-1 Signaling Pathway Plays a Crucial Role in the Myo-Inositol-Alleviated Aging in Caenorhabditis elegans.

Myo-Inositol (MI) has been shown to alleviate aging in Caenorhabditis (C). elegans. However, the mechanism by which MI alleviates aging remains unclear. In this study, we investigate whether MI can modulate the PI3K so as to attenuate the insulin/IGF-1 signaling (IIS) pathway and exert the longevity effect. The wild-type C. elegans and two mutants of AKT-1 and DAF-16 were used to explore the mechanism of MI so as to extend the lifespan, as well as to improve the health indexes of pharyngeal pumping and body bend, and an aging marker of autofluorescence in the C. elegans. We confirmed that MI could significantly extend the lifespan of C. elegans. MI also ameliorated the pharyngeal pumping and body bend and decreased autofluorescence. We further adopted the approach to reveal the loss-of-function mutants to find the signaling mechanism of MI. The functions of the lifespan-extending, health-improving, and autofluorescence-decreasing effects of MI disappeared in the AKT-1 and DAF-16 mutants. MI could also induce the nuclear localization of the DAF-16. Importantly, we found that MI could dramatically inhibit the phosphoinositide 3-kinase (PI3K) activity in a dose-dependent manner with an IC50 of 90.2 μM for the p110α isoform of the PI3K and 21.7 μM for the p110β. In addition, the downregulation of the PI3K expression and the inhibition of the AKT phosphorylation by MI was also obtained. All these results demonstrate that MI can inhibit the PI3K activity and downregulate the PI3K expression, and the attenuation of the IIS pathway plays a crucial role for MI in alleviating aging in C. elegans.

The reverse transcriptase inhibitor 3TC protects against age-related cognitive dysfunction.

Aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer's disease. Major hallmarks of brain aging include neuroinflammation/immune activation and reduced neuronal health/function. These processes contribute to cognitive dysfunction (a key risk factor for Alzheimer's disease), but their upstream causes are incompletely understood. Age-related increases in transposable element (TE) transcripts might contribute to reduced cognitive function with brain aging, as the reverse transcriptase inhibitor 3TC reduces inflammation in peripheral tissues and TE transcripts have been linked with tau pathology in Alzheimer's disease. However, the effects of 3TC on cognitive function with aging have not been investigated. Here, in support of a role for TE transcripts in brain aging/cognitive decline, we show that 3TC: (a) improves cognitive function and reduces neuroinflammation in old wild-type mice; (b) preserves neuronal health with aging in mice and Caenorhabditis elegans; and (c) enhances cognitive function in a mouse model of tauopathy. We also provide insight on potential underlying mechanisms, as well as evidence of translational relevance for these observations by showing that TE transcripts accumulate with brain aging in humans, and that these age-related increases intersect with those observed in Alzheimer's disease. Collectively, our results suggest that TE transcript accumulation during aging may contribute to cognitive decline and neurodegeneration, and that targeting these events with reverse transcriptase inhibitors like 3TC could be a viable therapeutic strategy.

Gut microbiota remodeling improves natural aging-related disorders through Akkermansia muciniphila and its derived acetic acid

Accumulating evidence indicates gut microbiota contributes to aging-related disorders. However, the exact mechanism underlying gut dysbiosis-related pathophysiological changes during aging remains largely unclear. In the current study, we first performed gut microbiota remodeling on old mice by fecal microbiota transplantation (FMT) from young mice, and then characterized the bacteria signature that was specifically altered by FMT. Our results revealed that FMT significantly improved natural aging-related systemic disorders, particularly exerted hepatoprotective effects, and improved glucose sensitivity, hepatosplenomegaly, inflammaging, antioxidative capacity and intestinal barrier. Moreover, FMT particularly increased the abundance of fecal A.muciniphila, which was almost nondetectable in old mice. Interestingly, A.muciniphila supplementation also exerted similar benefits with FMT on old mice. Notably, targeted metabolomics on short chain fatty acids (SCFAs) revealed that only acetic acid was consistently reversed by FMT. Then, acetic acid intervention exerted beneficial actions on both Caenorhabditis elegans and natural aging mice. In conclusion, our current study demonstrated that gut microbiota remodeling improved natural aging-related disorders through A.muciniphila and its derived acetic acid, suggesting that interventions with potent stimulative capacity on A. muciniphila growth and production of acetic acid was alternative and effective way to maintain healthy aging. Data availability statementThe data of RNAseq and 16 S rRNA gene sequencing can be accessed in NCBI with the accession number PRJNA848996 and PRJNA849355.

Age-dependent nuclear lipid droplet deposition is a cellular hallmark of aging in Caenorhabditis elegans.

Aging is the major risk factor for several life-threatening pathologies and impairs the function of multiple cellular compartments and organelles. Age-dependent deterioration of nuclear morphology is a common feature in evolutionarily divergent organisms. Lipid droplets have been shown to localize in most nuclear compartments, where they impinge on genome architecture and integrity. However, the significance of progressive nuclear lipid accumulation and its impact on organismal homeostasis remain obscure. Here, we implement non-linear imaging modalities to monitor and quantify age-dependent nuclear lipid deposition in Caenorhabditis elegans. We find that lipid droplets increasingly accumulate in the nuclear envelope, during aging. Longevity-promoting interventions, such as low insulin signaling and caloric restriction, abolish the rate of nuclear lipid accrual and decrease the size of lipid droplets. Suppression of lipotoxic lipid accumulation in hypodermal and intestinal nuclei is dependent on the transcription factor HLH-30/TFEB and the triglyceride lipase ATGL-1. HLH-30 regulates the expression of ATGL-1 to reduce nuclear lipid droplet abundance in response to lifespan-extending conditions. Notably, ATGL-1 localizes to the nuclear envelope and moderates lipid content in long-lived mutant nematodes during aging. Our findings indicate that the reduced ATGL-1 activity leads to excessive nuclear lipid accumulation, perturbing nuclear homeostasis and undermining organismal physiology, during aging.

The innate immune signaling component FBXC-58 mediates dietary restriction effects on healthy aging in Caenorhabditis elegans.

Dietary restriction (DR) is a highly effective and reproducible intervention that prolongs longevity in many organisms. The molecular mechanism of action of DR is tightly connected with the immune system; however, the detailed mechanisms and effective downstream factors of immunity that mediate the beneficial effects of DR on aging remain unknown. Here, to investigate the immune signaling that mediates DR effects, we used Caenorhabditis elegans, which has been widely used in research, to understand the underlying molecular mechanisms of aging and immunity. We found that the F-box gene, fbxc-58, a regulator of the innate immune response, is a novel mediator of DR effects on extending the health span of C. elegans. fbxc-58 is upregulated by DR and is necessary for DR-induced lifespan extension and physical health improvement in C. elegans. Furthermore, through DR, fbxc-58 prevents disintegration of the mitochondrial network in body wall muscle during aging. We found that fbxc-58 is a downstream target of the ZIP-2 and PHA-4 transcription factors, the well-known DR mediator, and fbxc-58 extends longevity in DR through an S6 kinase-dependent pathway. We propose that the novel DR effector, fbxc-58, could provide a new mechanistic understanding of the effects of DR on healthy aging and elucidate the signaling mechanisms that link immunity and DR effects with aging.

A worm's life: AMPK links muscle mitochondrial dynamics to physical fitness and healthy aging in Caenorhabditis elegans.

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Effects of Fisetin, a Plant-Derived Flavonoid, on Response to Oxidative Stress, Aging, and Age-Related Diseases in Caenorhabditis elegans.

Fisetin (3,3',4',7-tetrahydroxyflavone), a flavonoid abundant in various fruits and vegetables, including apple, strawberry, and onion, shows several beneficial effects such as anti-oxidant, anti-inflammatory, and anti-tumor effects. The free radical theory of aging suggests that age-related accumulation of oxidative damage is the major cause of aging and that decreasing cellular oxidative stress can regulate aging. Here, we investigated the effects of dietary supplementation with fisetin on the stress response, aging, and age-related diseases. Fisetin reduced the cellular ROS levels and increased the resistance to oxidative stress. However, the response to UV irradiation was not affected by fisetin. Both the mean and maximum lifespans were significantly extended by fisetin; lifespan extension by fisetin was accompanied by reduced fertility as a trade-off. Age-related decline in motility was also delayed by supplementation with fisetin. Amyloid beta-induced toxicity was markedly decreased by fisetin, which required DAF-16 and SKN-1. Reduced motility induced by a high-glucose diet was completely recovered by supplementation with fisetin, which was dependent on SKN-1. Using a Parkinson's disease model, we showed that degeneration of dopaminergic neurons was significantly inhibited by treatment with fisetin. Genetic analysis revealed that lifespan extension by fisetin was mediated by DAF-16-induced stress response and autophagy. These findings support the free radical theory of aging and suggest that fisetin can be a strong candidate for use in novel anti-aging anti-oxidant nutraceuticals.