Cellular Stress Response Pathways Research Articles

The Golgi Apparatus: A Voyage through Time, Structure, Function and Implication in Neurodegenerative Disorders.

This comprehensive review article dives deep into the Golgi apparatus, an essential organelle in cellular biology. Beginning with its discovery during the 19th century until today's recognition as an important contributor to cell function. We explore its unique organization and structure as well as its roles in protein processing, sorting, and lipid biogenesis, which play key roles in maintaining homeostasis in cellular biology. This article further explores Golgi biogenesis, exploring its intricate processes and dynamics that contribute to its formation and function. One key focus is its role in neurodegenerative diseases like Parkinson's, where changes to the structure or function of the Golgi apparatus may lead to their onset or progression, emphasizing its key importance in neuronal health. At the same time, we examine the intriguing relationship between Golgi stress and endoplasmic reticulum (ER) stress, providing insights into their interplay as two major cellular stress response pathways. Such interdependence provides a greater understanding of cellular reactions to protein misfolding and accumulation, hallmark features of many neurodegenerative diseases. In summary, this review offers an exhaustive examination of the Golgi apparatus, from its historical background to its role in health and disease. Additionally, this examination emphasizes the necessity of further research in this field in order to develop targeted therapeutic approaches for Golgi dysfunction-associated conditions. Furthermore, its exploration is an example of scientific progress while simultaneously offering hope for developing innovative treatments for neurodegenerative disorders.

The Potential of Fasting-Mimicking Diet as a Preventive and Curative Strategy for Alzheimer's Disease.

This review examines the potential of fasting-mimicking diets (FMDs) in preventing and treating Alzheimer's disease (AD). FMDs are low-calorie diets that mimic the physiological and metabolic effects of fasting, including the activation of cellular stress response pathways and autophagy. Recent studies have shown that FMDs can reduce amyloid-beta accumulation, tau phosphorylation, and inflammation, as well as improve cognitive function in animal models of AD. Human studies have also reported improvements in AD biomarkers, cognitive functions, and subjective well-being measures following FMDs. However, the optimal duration and frequency of FMDs and their long-term safety and efficacy remain to be determined. Despite these uncertainties, FMDs hold promise as a non-pharmacological approach to AD prevention and treatment, and further research in this area is warranted.

Exploiting inter-tissue stress signaling mechanisms to preserve organismal proteostasis during aging.

Aging results in a decline of cellular proteostasis capacity which culminates in the accumulation of phototoxic material, causing the onset of age-related maladies and ultimately cell death. Mechanisms that regulate proteostasis such as cellular stress response pathways sense disturbances in the proteome. They are activated to increase the expression of protein quality control components that counteract cellular damage. Utilizing invertebrate model organisms such as Caenorhabditis elegans, it has become increasingly evident that the regulation of proteostasis and the activation of cellular stress responses is not a cell autonomous process. In animals, stress responses are orchestrated by signals coming from other tissues, including the nervous system, the intestine and the germline that have a profound impact on determining the aging process. Genetic pathways discovered in C. elegans that facilitate cell nonautonomous regulation of stress responses are providing an exciting feeding ground for new interventions. In this review I will discuss cell nonautonomous proteostasis mechanisms and their impact on aging as well as ongoing research and clinical trials that can increase organismal proteostasis to lengthen health- and lifespan.

TXNIP: A key protein in the cellular stress response pathway and a potential therapeutic target.

Thioredoxin-interacting protein (TXNIP), which is also known as thioredoxin-binding protein 2 (TBP2), directly interacts with the major antioxidant protein thioredoxin (TRX) and inhibits its antioxidant function and expression. However, recent studies have demonstrated that TXNIP is a multifunctional protein with functions beyond increasing intracellular oxidative stress. TXNIP activates endoplasmic reticulum (ER) stress-mediated nucleotide-binding oligomerization domain (NOD)-like receptor protein-3 (NLRP3) inflammasome complex formation, triggers mitochondrial stress-induced apoptosis, and stimulates inflammatory cell death (pyroptosis). These newly discovered functions of TXNIP highlight its role in disease development, especially in response to several cellular stress factors. In this review, we provide an overview of the multiple functions of TXNIP in pathological conditions and summarize its involvement in various diseases, such as diabetes, chronic kidney disease, and neurodegenerative diseases. We also discuss the potential of TXNIP as a therapeutic target and TXNIP inhibitors as novel therapeutic drugs for treating these diseases.

Mitigating Oxidative Stress in Perinatal Cells: A Critical Step toward an Optimal Therapeutic Use in Regenerative Medicine.

Oxidative stress (OS) occurs when the production of reactive oxygen species (ROS) is not balanced by the body's antioxidant defense system. OS can profoundly affect cellular health and function. ROS can have a profound negative impact on cells that undergo a predestined and time-regulated process of proliferation or differentiation, such as perinatal stem cells. Due to the large-scale employment of these immunotolerant stem cells in regenerative medicine, it is important to reduce OS to prevent them from losing function and increase their application in the regenerative medicine field. This goal can be achieved through a variety of strategies, such as the use of antioxidants and other compounds that can indirectly modulate the antioxidant defense system by enhancing cellular stress response pathways, including autophagy and mitochondrial function, thereby reducing ROS levels. This review aims to summarize information regarding OS mechanisms in perinatal stem cells and possible strategies for reducing their deleterious effects.

Surviving and Adapting to Stress: Translational Control and the Integrated Stress Response.

Significance: Organisms adapt to changing environments by engaging cellular stress response pathways that serve to restore proteostasis and enhance survival. A primary adaptive mechanism is the integrated stress response (ISR), which features phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2). Four eIF2α kinases respond to different stresses, enabling cells to rapidly control translation to optimize management of resources and reprogram gene expression for stress adaptation. Phosphorylation of eIF2 blocks its guanine nucleotide exchange factor, eIF2B, thus lowering the levels of eIF2 bound to GTP that is required to deliver initiator transfer RNA (tRNA) to ribosomes. While bulk messenger RNA (mRNA) translation can be sharply lowered by heightened phosphorylation of eIF2α, there are other gene transcripts whose translation is unchanged or preferentially translated. Among the preferentially translated genes is ATF4, which directs transcription of adaptive genes in the ISR. Recent Advances and Critical Issues: This review focuses on how eIF2α kinases function as first responders of stress, the mechanisms by which eIF2α phosphorylation and other stress signals regulate the exchange activity of eIF2B, and the processes by which the ISR triggers differential mRNA translation. To illustrate the synergy between stress pathways, we describe the mechanisms and functional significance of communication between the ISR and another key regulator of translation, mammalian/mechanistic target of rapamycin complex 1 (mTORC1), during acute and chronic amino acid insufficiency. Finally, we discuss the pathological conditions that stem from aberrant regulation of the ISR, as well as therapeutic strategies targeting the ISR to alleviate disease. Future Directions: Important topics for future ISR research are strategies for modulating this stress pathway in disease conditions and drug development, molecular processes for differential translation and the coordinate regulation of GCN2 and other stress pathways during physiological and pathological conditions. Antioxid. Redox Signal. 39, 351-373.

MicroRNAs in Age-Related Proteostasis and Stress Responses.

Aging is associated with the accumulation of damaged and misfolded proteins through a decline in the protein homeostasis (proteostasis) machinery, leading to various age-associated protein misfolding diseases such as Huntington's or Parkinson's. The efficiency of cellular stress response pathways also weakens with age, further contributing to the failure to maintain proteostasis. MicroRNAs (miRNAs or miRs) are a class of small, non-coding RNAs (ncRNAs) that bind target messenger RNAs at their 3'UTR, resulting in the post-transcriptional repression of gene expression. From the discovery of aging roles for lin-4 in C. elegans, the role of numerous miRNAs in controlling the aging process has been uncovered in different organisms. Recent studies have also shown that miRNAs regulate different components of proteostasis machinery as well as cellular response pathways to proteotoxic stress, some of which are very important during aging or in age-related pathologies. Here, we present a review of these findings, highlighting the role of individual miRNAs in age-associated protein folding and degradation across different organisms. We also broadly summarize the relationships between miRNAs and organelle-specific stress response pathways during aging and in various age-associated diseases.

Physiological aspect of apoptosis-regulating microRNAs expressions during fasting.

Fasting is an activity that requires a certain calorie restriction without consuming food or drinks for a certain period of daytime. However, fasting triggers many complex events, including activating cellular stress response pathways, autophagy promotion, apoptosis pathways, and a change in hormonal balance. Among the many events affecting the regulation of apoptosis, the expression of microRNAs (miRNAs) plays an important role. Therefore, we aimed to investigate the levels and importance of miRNA expression in fasting. The expressions of 19 miRNAs regulating different pathways from saliva samples, isolated by matching healthy university students (n = 34) as group 1 (fasting for 17 consecutive hours) and group 2 (testing 70 minutes after meal consumption), were examined using the real-time PCR method. In fasting, modulation of apoptotic pathways by miRNAs triggers anti-pathogenic effects, and the adaptation of abnormal cells in the body decreases. For this reason, vital diseases, such as cancer, can be treated by preventing the proliferation and growth of cancerous cells by increasing programmed cell death due to the downregulation expression mechanism of miRNAs. Our study aims to improve the knowledge about the mechanisms and functions of miRNAs in various apoptosis pathways during fasting and may be a model for further future physiological and pathological studies.

The functional role of Ire1 in regulating autophagy and proteasomal degradation under prolonged proteotoxic stress.

Inhibition of endoribonuclease/kinase Ire1 has shown beneficial effects in many proteotoxicity-induced pathology models. The mechanism by which this occurs has not been elucidated completely. Using a proteotoxic yeast model of Huntington's disease, we show that the deletion of Ire1 led to lower protein aggregation at longer time points. The rate of protein degradation was higher in ΔIre1 cells. We monitored the two major protein degradation mechanisms in the cell. The increase in expression of Rpn4, coding for the transcription factor controlling proteasome biogenesis, was higher in ΔIre1 cells. The chymotrypsin-like proteasomal activity was also significantly enhanced in these cells at later time points of aggregation. The gene and protein expression levels of the autophagy gene Atg8 were higher in ΔIre1 than in wild-type cells. Significant increase in autophagy flux was also seen in ΔIre1 cells at later time points of aggregation. The results suggest that the deletion of Ire1 activates UPR-independent arms of the proteostasis network, especially under conditions of aggravated stress. Thus, the inhibition of Ire1 may regulate UPR-independent cellular stress-response pathways under prolonged stress.

Plant-based Natural inhibitors of human liver carcinogenesis: A mechanistic overview, focusing on hepatitis B and hepatitis C viruses

Hepatitis B and C viruses can lead to serious complications such as hepatic fibrosis, liver cirrhosis, and hepatocellular carcinoma (HCC) and are therefore responsible for a significant portion of liver cancer cases worldwide, with over 1.3 million deaths annually. The mechanisms by which hepatitis viruses contribute to HCC include DNA integration into the host genome, metabolic reprogramming, induction of the cellular stress response pathway, and interference with tumour suppressors. HBV is a DNA virus from the Hepadnaviridae family, and HCV is an RNA virus from the Flaviviridae family. Both viruses are transmitted through contact with infected bodily fluids, such as blood or sexual fluids. It is important to get tested for hepatitis B and C and to seek treatment as early as possible to prevent the progression to liver cancer. While there is a vaccine available for Hepatitis B, there is currently no vaccine for Hepatitis C. But some natural medicines have demonstrated antiviral activity against the hepatitis B and C viruses. Therefore, it is important to explore natural alternatives for the treatment of this disease. This review aims to summarise the pathogenesis of hepatitis B and C and their link to hepatocellular carcinoma, as well as to highlight natural compounds with the potential to treat hepatitis through various mechanisms at different stages of infection. These natural compounds may offer an alternative to chemical-based medications in the treatment and control of hepatitis by inhibiting or disrupting the entry, activity, or replication of the virus within the host.

Chronic Kidney Disease Induces Proarrhythmic Remodeling.

Patients with chronic kidney disease (CKD) are at increased risk of developing cardiac arrhythmogenesis and sudden cardiac death; however, the basis for this association is incompletely known. Here, using murine models of CKD, we examined interactions between kidney disease progression and structural, electrophysiological, and molecular cardiac remodeling. C57BL/6 mice with adenine supplemented in their diet developed progressive CKD. Electrocardiographically, CKD mice developed significant QT prolongation and episodes of bradycardia. Optical mapping of isolated-perfused hearts using voltage-sensitive dyes revealed significant prolongation of action potential duration with no change in epicardial conduction velocity. Patch-clamp studies of isolated ventricular cardiomyocytes revealed changes in sodium and potassium currents consistent with action potential duration prolongation. Global transcriptional profiling identified dysregulated expression of cellular stress response proteins RBM3 (RNA-binding motif protein 3) and CIRP (cold-inducible RNA-binding protein) that may underlay the ion channel remodeling. Unexpectedly, we found that female sex is a protective factor in the progression of CKD and its cardiac sequelae. Our data provide novel insights into the association between CKD and pathologic proarrhythmic cardiac remodeling. Cardiac cellular stress response pathways represent potential targets for pharmacologic intervention for CKD-induced heart rhythm disorders.

Capturing time-dependent activation of genes and stress-response pathways using transcriptomics in iPSC-derived renal proximal tubule cells

Transcriptomic analysis is a powerful method in the utilization of New Approach Methods (NAMs) for identifying mechanisms of toxicity and application to hazard characterization. With this regard, mapping toxicological events to time of exposure would be helpful to characterize early events. Here, we investigated time-dependent changes in gene expression levels in iPSC-derived renal proximal tubular-like cells (PTL) treated with five diverse compounds using TempO-Seq transcriptomics with the aims to evaluate the application of PTL for toxicity prediction and to report on temporal effects for the activation of cellular stress response pathways. PTL were treated with either 50 μM amiodarone, 10 μM sodium arsenate, 5 nM rotenone, or 300 nM tunicamycin over a temporal time course between 1 and 24 h. The TGFβ-type I receptor kinase inhibitor GW788388 (1 μM) was used as a negative control. Pathway analysis revealed the induction of key stress-response pathways, including Nrf2 oxidative stress response, unfolding protein response, and metal stress response. Early response genes per pathway were identified much earlier than 24 h and included HMOX1, ATF3, DDIT3, and several MT1 isotypes. GW788388 did not induce any genes within the stress response pathways above, but showed deregulation of genes involved in TGFβ inhibition, including downregulation of CYP24A1 and SERPINE1 and upregulation of WT1. This study highlights the application of iPSC-derived renal cells for prediction of cellular toxicity and sheds new light on the temporal and early effects of key genes that are involved in cellular stress response pathways.

Editors' Selections from Relevant Scientific Publications

Editors' Selections from Relevant Scientific Publications

PVT1 is a stress-responsive lncRNA that drives ovarian cancer metastasis and chemoresistance.

Metastatic growth of ovarian cancer cells into the peritoneal cavity requires adaptation to various cellular stress factors to facilitate cell survival and growth. Here, we demonstrate the role of PVT1, one such stress induced long non-coding RNA, in ovarian cancer growth and metastasis. PVT1 is an amplified and overexpressed lncRNA in ovarian cancer with strong predictive value for survival and response to targeted therapeutics. We find that expression of PVT1 is regulated by tumor cells in response to cellular stress, particularly loss of cell-cell contacts and changes in matrix rigidity occurring in a YAP1-dependent manner. Induction of PVT1 promotes tumor cell survival, growth, and migration. Conversely, reducing PVT1 levels robustly abrogates metastatic behavior and tumor cell dissemination in cell lines and syngeneic transplantation models in vivo. We find that reducing PVT1 causes widespread changes in the transcriptome leading to alterations in cellular stress response and metabolic pathways including doxorubicin metabolism, which impacts chemosensitivity. Together, these findings implicate PVT1 as a promising therapeutic target to suppress metastasis and chemoresistance in ovarian cancer.

Mapping the dynamics of Nrf2 antioxidant and NFκB inflammatory responses by soft electrophilic chemicals in human liver cells defines the transition from adaptive to adverse responses

A comprehensive understanding of the dynamic activation and crosstalk between different cellular stress response pathways that drive cell adversity is crucial in chemical safety assessment. Various chemicals have electrophilic properties that drive cell injury responses in particular oxidative stress signaling and inflammatory signaling. Here we used bacterial artificial chromosome-based GFP cellular stress reporters with live cell confocal imaging, to systematically monitor the differential modulation of the dynamics of stress pathway activation by six different soft electrophiles: sulforaphane, andrographolide, diethyl maleate, CDDO-Me, ethacrynic acid and tert-butyl hydroquinone. The various soft electrophiles showed differential potency and dynamics of Nrf2 activation and nuclear translocation. These differences in Nrf2 dynamics correlated with distinct activation pattern of Nrf2 downstream targets SRNX1 and HMOX1. All soft electrophiles caused a strong dose dependent suppression of a cytokine-induced NFĸB response represented by suppression of NFĸB nuclear oscillation and inhibition of the downstream target gene activation A20 and ICAM1, which followed the potency of Nrf2 modulation but occurred at higher concentration close to saturation of Nrf2 activation. RNAi-based depletion of RelA resulted in a prolonged presence of Nrf2 in the nucleus after soft electrophile treatment; depletion of Nrf2 caused the induction of NFĸB signaling and activation of its downstream targets A20 and ICAM1. A systematic transcriptome analysis confirmed these effects by soft electrophiles on Nrf2 and NFκB signaling crosstalk in human induced-pluripotent stem cell-derived hepatocyte-like cells. Altogether our data indicate that modulation of Nrf2 by soft electrophiles may have consequences for efficient inflammatory signaling.

Eosinophils, Hypoxia-Inducible Factors, and Barrier Dysfunction in Functional Dyspepsia.

Functional dyspepsia (FD) is a highly prevalent disorder of gut-brain interaction (DGBI), previously known as a functional gastrointestinal disorder. Characterized by early satiety, postprandial fullness, and/or epigastric pain or burning, diagnosis depends on positive symptomatology and exclusion of obvious structural diseases. A subtle inflammatory phenotype has been identified in FD patients, involving an increase in duodenal mucosal eosinophils, and imbalances in the duodenal gut microbiota. A dysregulated epithelial barrier has also been well described in FD and is thought to be a contributing factor to the low-grade duodenal inflammation observed, however the mechanisms underpinning this are poorly understood. One possible explanation is that alterations in the microbiota and increased immune cells can result in the activation of cellular stress response pathways to perpetuate epithelial barrier dysregulation. One such cellular response pathway involves the stabilization of hypoxia-inducible factors (HIF). HIF, a transcriptional protein involved in the cellular recognition and adaptation to hypoxia, has been identified as a critical component of various pathologies, from cancer to inflammatory bowel disease (IBD). While the contribution of HIF to subtle inflammation, such as that seen in FD, is unknown, HIF has been shown to have roles in regulating the inflammatory response, particularly the recruitment of eosinophils, as well as maintaining epithelial barrier structure and function. As such, we aim to review our present understanding of the involvement of eosinophils, barrier dysfunction, and the changes to the gut microbiota including the potential pathways and mechanisms of HIF in FD. A combination of PubMed searches using the Mesh terms functional dyspepsia, functional gastrointestinal disorders, disorders of gut-brain interaction, duodenal eosinophilia, barrier dysfunction, gut microbiota, gut dysbiosis, low-grade duodenal inflammation, hypoxia-inducible factors (or HIF), and/or intestinal inflammation were undertaken in the writing of this narrative review to ensure relevant literature was included. Given the findings from various sources of literature, we propose a novel hypothesis involving a potential role for HIF in the pathophysiological mechanisms underlying FD.

Iron accumulation induces oxidative stress, while depressing inflammatory polarization in human iPSC-derived microglia.

SummaryIron accumulation in microglia has been observed in Alzheimer’s disease and other neurodegenerative disorders and is thought to contribute to disease progression through various mechanisms, including neuroinflammation. To study this interaction, we treated human induced pluripotent stem cell-derived microglia (iPSC-MG) with iron, in combination with inflammatory stimuli such as interferon gamma (IFN-γ) and amyloid β. Both IFN-γ and iron treatment increased labile iron levels, but only iron treatment led to a consistent increase of ferritin levels, reflecting long-term iron storage. Therefore, in iPSC-MG, ferritin appeared to be regulated by iron revels rather than inflammation. Further investigation showed that while IFN-γ induced pro-inflammatory activation, iron treatment dampened both classic pro- and anti-inflammatory activation on a transcriptomic level. Notably, iron-loaded microglia showed strong upregulation of cellular stress response pathways, the NRF2 pathway, and other oxidative stress pathways. Functionally, iPSC-MG exhibited altered phagocytosis and impaired mitochondrial metabolism following iron treatment. Collectively, these data suggest that in MG, in contrast to current hypotheses, iron treatment does not result in pro-inflammatory activation, but rather dampens it and induces oxidative stress.

Measuring AMPK Activity in Vivo Using a Genetically‐Encoded Biosensor

Adenosine monophosphate‐activated kinase (AMPK) is a highly conserved heterotrimeric protein complex that functions in a broad spectrum of cellular stress response pathways. Most work investigating the cellular dynamics of AMPK activity has been limited to either whole‐organ/tissue or, in the case of smaller genetic models like Caenorhabditis elegans, whole‐organism analyses. Some limitations of these approaches include: 1) An inability to observe cellular heterogeneity of AMPK activation; 2) a lack of the temporal dynamics; 3) an inability to correlate AMPK dynamics with physiological states of a living organism. Thus, we sought to adapt a genetically‐coded AMPK biosensor, called AMPKAR‐EV (Kongaya et al., 2017), for use in C. elegans, which is transparent and genetically tractable. The AMPKAR‐EV biosensor uses fluorescence resonance energy transfer (FRET) to report AMPK phosphorylation of substrates. We expressed codon‐adapted AMPKAR‐EV in C. elegans and made three separate transgenic lines expressing it in intestines, body wall muscles, and neurons. As expected, we find that the biosensor responds to conditions that promote AMPK activation. We crossed the lines expressing AMPKAR‐EV in the intestines into a number of different genetic mutants, which we either generated using CRISPR or obtained from previous studies. For context, work in mammals suggests that protein kinase A (PKA) phosphorylates AMPK at serine 173 (S173 ‐ inhibitory site) and prevents catalytic phosphorylation at threonine 172 (T172 ‐ activation site). These sites are conserved to C. elegans but located at serine 244 (S244) and threonine 243 (T243) respectively; however, the significance of these regulatory sites have not been specifically studied. To test these mechanisms more precisely, we made two C. elegans strains that also express AMPKAR‐EV, one that alters the activation site (aak‐2(T243A)) and another that alters the inhibitory site (aak‐2(S244G)). The third strain we constructed expresses AMPKAR‐EV in the kin‐2(ce179) mutant background, which exhibits constitutively active PKA. Using these strains we are optimizing AMPKAR‐EV in vivo and testing the hypothesis that PKA inhibits AMPK at the S244 inhibitory site, which prevents its phosphorylation at the activation site. We envision that AMPKAR‐EV will be of broad use in C. elegans as an organism well‐known for its study of behavior, aging, and longevity.

The emerging role of dipeptidyl peptidase 3 in pathophysiology.

Dipeptidyl peptidase 3 (DPP3), a zinc-dependent aminopeptidase, is a highly conserved enzyme among higher animals. The enzyme cleaves dipeptides from the N-terminus of tetra- to decapeptides, thereby taking part in activation as well as degradation of signalling peptides critical in physiological and pathological processes such as blood pressure regulation, nociception, inflammation and cancer. Besides its catalytic activity, DPP3 moonlights as a regulator of the cellular oxidative stress response pathway, e.g., the Keap1-Nrf2 mediated antioxidative response. The enzyme is also recognized as a key modulator of the renin-angiotensin system. Recently, DPP3 has been attracting growing attention within the scientific community, which has significantly augmented our knowledge of its physiological relevance. Herein, we review recent advances in our understanding of the structure and catalytic activity of DPP3, with a focus on attributing its molecular architecture and catalytic mechanism to its wide-ranging biological functions. We further highlight recent intriguing reports that implicate a broader role for DPP3 as a valuable biomarker in cardiovascular and renal pathologies and furthermore discuss its potential as a promising drug target.

Hijacking Cellular Stress Responses to Promote Lifespan.

Organisms are constantly exposed to stress both from the external environment and internally within the cell. To maintain cellular homeostasis under different environmental and physiological conditions, cell have adapted various stress response signaling pathways, such as the heat shock response (HSR), unfolded protein responses of the mitochondria (UPRMT), and the unfolded protein response of the endoplasmic reticulum (UPRER). As cells grow older, all cellular stress responses have been shown to deteriorate, which is a major cause for the physiological consequences of aging and the development of numerous age-associated diseases. In contrast, elevated stress responses are often associated with lifespan extension and amelioration of degenerative diseases in different model organisms, including C. elegans. Activating cellular stress response pathways could be considered as an effective intervention to alleviate the burden of aging by restoring function of essential damage-clearing machinery, including the ubiquitin-proteosome system, chaperones, and autophagy. Here, we provide an overview of newly emerging concepts of these stress response pathways in healthy aging and longevity with a focus on the model organism, C. elegans.