You will be presented with the abstract, introduction, and discussion section from a biomedical research article. Your task is to create a summary that a layperson can understand, capturing the essence of the research article. Keep essential scientific terms, but ensure that the language remains clear and the concepts are explained in an uncomplicated manner.

Title: HIF-1 Modulates Dietary Restriction-Mediated Lifespan Extension via IRE-1 in Caenorhabditis elegans}
Article:
Abstract:
Dietary restriction( DR) extends lifespan in various species and also slows the onset of age-related diseases. Previous studies from flies and yeast have demonstrated that the target of rapamycin( TOR) pathway is essential for longevity phenotypes resulting from DR. TOR is a conserved protein kinase that regulates growth and metabolism in response to nutrients and growth factors. While some of the downstream targets of TOR have been implicated in regulating lifespan, it is still unclear whether additional targets of this pathway also modulate lifespan. It has been shown that the hypoxia inducible factor-1( HIF-1) is one of the targets of the TOR pathway in mammalian cells. HIF-1 is a transcription factor complex that plays key roles in oxygen homeostasis, tumor formation, glucose metabolism, cell survival, and inflammatory response. Here, we describe a novel role for HIF-1 in modulating lifespan extension by DR in Caenorhabditis elegans. We find that HIF-1 deficiency results in extended lifespan, which overlaps with that by inhibition of the RSKS-1/S6 kinase, a key component of the TOR pathway. Using a modified DR method based on variation of bacterial food concentrations on solid agar plates, we find that HIF-1 modulates longevity in a nutrient-dependent manner. The hif-1 loss-of-function mutant extends lifespan under rich nutrient conditions but fails to show lifespan extension under DR. Conversely, a mutation in egl-9, which increases HIF-1 activity, diminishes the lifespan extension under DR. This deficiency is rescued by tissue-specific expression of egl-9 in specific neurons and muscles. Increased lifespan by hif-1 or DR is dependent on the endoplasmic reticulum( ER) stress regulator inositol-requiring protein-1( IRE-1) and is associated with lower levels of ER stress. Therefore, our results demonstrate a tissue-specific role for HIF-1 in the lifespan extension by DR involving the IRE-1 ER stress pathway.
Introduction:
Dietary restriction( DR) has been shown to extend lifespan in various species. It also slows the onset of a number of age-related diseases in rodents. Conservation of signaling pathways in multiple species and the rapidity with which lifespan studies can be carried out in simple model organisms make them powerful tools to understand aging and age-related diseases in humans. Identification of genes involved in DR response will therefore provide potential targets for treatments of age–associated diseases and the extension of healthful lifespan in humans. The quest to understand the mechanisms of DR-induced lifespan extension has led to intensive studies in the primary genetic model organisms Saccharomyces cerevisiae, Caenorhabditis elegans, and Drosophila melanogaster, in which the robust effects of lifespan extension by DR can be observed[1]–[5]. Evidence from previous studies has identified the TOR pathway as a key mediator of nutrient-modulated lifespan changes in flies[6], yeast[7] and worms[8], although the involvement of TOR in response to DR in C. elegans is still controversial[8],[9]. TOR is a conserved protein kinase that plays essential roles in regulating growth and metabolism in response to nutrients and growth factors[10]. TOR interacts with the regulatory associated protein of TOR( raptor) to permit transduction of nutrient signals to downstream cellular processes, including mRNA translation, ribosome synthesis, expression of metabolism-related genes and autophagy[11]. TOR promotes protein synthesis by activating S6K and inhibiting eukaryotic translation initiation factor 4E-binding protein( 4E-BP). Recent studies have shown that regulation of mRNA translation plays critical roles in lifespan determination in multiple species[9],[12]–[19]. In C. elegans, mutations in the TOR ortholog let-363 lead to developmental arrest at the third larval stage and intestinal atrophy[20]. Inhibition of let-363 by RNAi extends lifespan[8],[12],[21]. The larval arrest phenotype was also observed from homozygous mutants of daf-15, which encodes the C. elegans ortholog of raptor. Heterozygous mutants of daf-15 have increased lifespan[22]. Inactivation of rsks-1, which encodes the C. elegans ortholog of S6K[23], significantly extends lifespan[12],[13]. Although it is well established that the C. elegans TOR pathway modulates lifespan, it is still unclear whether TOR affects DR-mediated lifespan extension. There have been two reports with opposite results on whether inhibition of let-363 by RNAi further extends lifespan of the eat-2 mutant, which serves as a genetic mimic of DR[8],[9]. Multiple studies in mammalian and Drosophila cells have implicated the transcription factor HIF-1 as a target of the TOR pathway[24]–[27]. HIF-1 is regulated at the mRNA translation level, and enhanced levels of HIF-1 are associated with increased TOR and S6K activities under both normoxic and hypoxic conditions[24],[26],[28],[29]. HIF-1 is a heterodimeric transcriptional complex that contains HIF-1α and HIF-1β. It plays essential roles in oxygen homeostasis[30] and is also regulated by other physiological stimuli like heat acclimation[31], acidosis[32], nitric oxide[33], inflammation[34] and oxidative stress[35],[36]. Under normoxia, specific proline residues of HIF-1α are hydroxylated by the PH superfamily of dioxygenase encoded by egl-9 in C. elegans. Hydroxylated HIF-1α is subject to von Hippel Lindau( pVHL)-mediated proteasome degradation. Under hypoxia, the hydroxylation modification declines and HIF-1α is stabilized for its transcriptional activities[37]. HIF-1 helps cells adapt to low-oxygen stress by regulating angiogenesis, glycolysis, and cell survival[30]. HIF-1 overexpression is frequently detected in solid tumors due to intratumoral hypoxia and genetic mutations, and inhibition of HIF-1 can prevent tumor growth[38],[39]. In C. elegans, hif-1 encodes the HIF-1α ortholog, which has been connected to multiple biological processes, including hypoxia response[37],[40], adaption to heat stress[31], oxygen preference[41],[42], and neuronal migration[43]. Despite the well-characterized links between HIF-1 and cancer, metabolism, and cell survival, it is not known whether HIF-1 is directly involved in organismal aging. In this study, we investigated the role of HIF-1 in lifespan determination in C. elegans. We demonstrate that HIF-1 functions downstream of S6K to modulate DR-dependent lifespan extension in specific neurons and muscles via the IRE-1 ER stress pathway.
Discussion:
Previous studies have identified HIF-1 as a key regulator in various cellular processes, including stress resistance, glucose metabolism, angiogenesis and cell death. Despite the well-characterized HIF-1 functions in age-associated physiological processes and the regulation of HIF-1 by known lifespan determinants, such as TOR and S6K, it has not been clear whether HIF-1 is involved in organismal aging. In this study, we found that a deletion mutant of hif-1 shows significant lifespan extension in C. elegans. Genetic epistasis experiments indicate that HIF-1 functions downstream of the nutrient-responsive TOR-S6K pathway to modulate lifespan. Using a modified sDR regime, we found that HIF-1 is involved in DR-mediated lifespan regulation, with overexpression of HIF-1 diminishes lifespan extension under DR. Recent studies in C. elegans have identified novel genetic pathways that determine the beneficial effects of DR[49],[53]–[55],[68]. Using different regimens to restrict nutrients intake, previous studies have identified key regulators of DR-dependent lifespan extension, including transcription factors PHA-4, SKN-1, HSF-1 and the cellular energy homeostasis regulator AMP-activated protein kinase( AMPK). It is very likely that the maximal lifespan extension by DR is not achieved by regulating a single genetic pathway but that multiple pathways act together to mediate the lifespan effect of DR[69],[70]. The TOR pathway has been shown to play important roles in DR-dependent lifespan extension in D. melanogaster[6] and S. cerevisiae[7]. Our study underscores the importance of the TOR-S6K pathway as a conserved mediator of lifespan extension by DR in multiple species. One of the most important questions about DR is how animals sense reduced nutrients to adjust gene expression, metabolism and behavior for extended survival. It has been shown that the SKN-1 transcription factor functions in ASI neurons to mediate liquid DR-induced longevity by an endocrine mechanism[53]. Using transgenic animals that express egl-9 cDNA with various tissue-specific promoters in the egl-9 mutant background[41], we found that restoring EGL-9 function in serotonergic neurons( ADF, NSM), body wall muscle and pharyngeal muscle can rescue lifespan phenotypes of egl-9 under DR. Serotonin is a neurotransmitter that regulates feeding, reproduction, and fat metabolism in C. elegans.[71],[72]. Recently, serotonin signaling has also been connected to aging in C. elegans[73],[74]. It will be interesting to examine whether HIF-1 regulates serotonin signaling, and whether serotonin signaling is involved in DR-dependent lifespan extension in C. elegans. A previous study has shown that muscle decline is one of the major physiological causes of C. elegans aging[62]. Whether DR and HIF-1 affect muscle structure and function during aging needs to be further investigated. The pharynx is the food intake organ of C. elegans. The FOXA transcription factor PHA-4 plays essential roles in pharyngeal development[75]. Interestingly, PHA-4 is required for lifespan extension by DR[54] and by a mutation in S6K[76], but lifespan extension by hif-1 is not dependent on PHA-4. These experiments suggest that there may be multiple pathways downstream of TOR/S6K that mediate lifespan extension in response to DR. Abundant evidence has indicated that ER stress and protein homeostasis are important for aging[17],[59],[77],[78]. ER stress is caused by an overload of unfolded/misfolded proteins to ER[64]. ER stress activates the unfolded protein response through three signaling pathways transduced by IRE1, PERK, and ATF6. We showed that lifespan extension by DR or hif-1 requires functional IRE-1 and XBP-1 ER stress signaling. Reduced nutrients are associated with lower ER stress, which is consistent with findings in mice that increased nutrient intake or TOR activation is linked to increased ER stress[65],[79]. Our results implicating the role of ER stress in DR-mediated lifespan extension in C. elegans are also consistent with findings from S. cerevisae, in which the lifespan extension by DR was found to be partially dependent on GCN4[17], which functions downstream of PERK in the unfolded protein response[80]. Our work describes a novel role for ER signaling in aging and DR-dependent lifespan extension, examination of which may help explain how protein homeostasis determines lifespan and age-related diseases. DR has not only been shown to extend lifespan in rodents but also is one of the most robust methods to reduce tumorigenesis in mice[81]. However, the mechanisms by which DR causes this protection have not been elucidated. Our results implicate HIF-1 as a potential target in mediating the protective effects of DR on tumorigenesis in mammals. HIF-1 overexpression is frequently detected in various tumors due to intratumoral hypoxia and genetic mutations. HIF-1 owes its oncogenic properties to pleiotropic effects on a variety of cellular processes, including survival under hypoxia, angiogenesis, metastasis and glucose metabolism. Inhibition of HIF-1 has been proven to be an efficient way to prevent tumor growth, and HIF-1 is being extensively studied as an important target in cancer therapy. Our study suggests an important role for HIF-1 as an oncogene in the context of aging and nutrient sensing, which are both key risk factors in tumor formation.
Dietary restriction ( DR ) is one of the most robust environmental manipulations that extend lifespan in various species . DR has also been shown to slow the onset of a number of age-related diseases . Studies in model organisms like C . elegans can be used to uncover biological mechanisms that determine the beneficial effects of DR . Previous studies suggest that the nutrient-sensing target of rapamycin ( TOR ) pathway is required for DR-mediated lifespan extension . However , the downstream mechanisms by which TOR modulates lifespan remain unclear . In mammalian cells , TOR and the downstream S6 kinase ( S6K ) activate expression of the hypoxia-inducible factor-1 ( HIF-1 ) , which is frequently up-regulated in various tumors . Using C . elegans as a model system , we characterized novel functions of HIF-1 in aging . We find that inhibition of HIF-1 extends lifespan under rich nutrient conditions , whereas enhanced levels of HIF-1 only allow partial lifespan extension by DR . We also demonstrated that increased lifespan by hif-1 or DR depends on the endoplasmic reticulum ( ER ) stress regulator inositol-requiring protein-1 ( IRE-1 ) and is associated with lower levels of ER stress , which is caused by overloading of misfolded/unfolded proteins to ER . Thus , our results support the idea that HIF-1–mediated changes in protein homeostasis play a key role in the lifespan extension by DR .