Metformin has been demonstrated to extend lifespan in various model organisms, and its molecular effects are observed in the cytoplasm and multiple organelles, including mitochondria. However, its association with the unfolded protein response (UPR) and its impact on stress resistance and locomotion remain uncertain. In this study, metformin was found to exert differential influences on both UPR^mt and UPR^er. The correlation between metformin’s lifespan-mediating effect and its interaction with UPRs was also inconsistent. We identified a metformin-mediated lifespan extension in wild-type C. elegans and in UPR^mt-activated tomm-22 and cco-1 RNAi worms. Metformin suppressed the UPR^mt without compromising the lifespan extension observed in tomm-22 worms. Conversely, metformin did not affect the UPR^mt but extended the lifespan of long-lived cco-1 RNAi worms. Furthermore, we investigated the effects of metformin on UPR^er-activated nematodes. We observed that metformin exhibited a slight increase in the UPR^er in mdt-15 RNAi worms and failed to induce lifespan extension. Surprisingly, metformin appeared to mediate lifespan extension in tmem-131 RNAi worms while suppressing the UPR^er. Notably, the correlation between thermotolerance, oxidative stress resistance, and the lifespan effects of metformin in UPR-activated worms was inconsistent. Activation of UPRs, but not metformin treatment, enhanced the locomotor phenotype of these worms.

Caenorhabditis elegans has served as a model for the unfolded protein response of the endoplasmic reticulum (UPR-ER) and, separately, the oxidative stress response coordinated by SKN-1/Nrf. The oxidative protein folding in the ER generates reactive oxygen species, which is one reason why these systems are frequently studied together. Additionally, numerous stressors activate both pathways simultaneously. Although these molecular chaperones are critical to both processes, current research rarely considers them as an integrative concept, instead categorizing the interaction strictly within different pathway mechanisms. This review focuses on the chaperone systems themselves, including the HSP-4 and protein disulfide isomerases that are located in the ER, the HSP-70 family that resides in the cytoplasm and is controlled by HSF-1, and HSP-6 and HSP-60 that function in the mitochondria and are regulated by ATFS-1. Oxidative stress interacts with each compartment in a manner that is mechanistically distinct. This corresponds to direct redox chemistry in the ER, transcriptional coupling by SKN-1, and compartment-specific ROS-sensing evidence in the mitochondria and cytoplasm. Oxidative stress and chaperone induction converge through multiple independent pathways rather than a single sequential pathway, and this convergence deteriorates with age in a pathway- and tissue-specific manner, as shown by studies focusing on translational chaperone loss, particulate matter exposure, and proteasome-mediated degradation. Finally, we address some outstanding issues, such as the translational relevance to human diseases associated with ER stress and the functioning of redox-regulated chaperone mechanisms in C. elegans.

Selenium (Se) is a trace element with a narrow margin between beneficial effects and stress from toxic effects. The determinants of the transition from selenium adequacy to toxicity remain unknown. Moreover, the roles of selenoproteins and other adaptive responses also remain unclear. The effects of dynamic and localized redox fluctuations on survival and neurodegeneration also require further investigation. To better understand the underlying mechanisms, several studies utilized the nematode Caenorhabditis elegans (C. elegans) as a model. This review systematically addresses pivotal mechanistic controversies. Thioredoxin reductase-1 (TRXR-1) is the only protein in a small amount of the selenoproteome, and it also has a fully conserved selenocysteine insertion mechanism. Moreover, this systematic review also incorporates the current understanding of the molecular factors that determine selenium homeostasis, ranging from neurotoxicological diseases to biosynthetic circumstances. TRXR-1 supports health benefits such as enhance lipid metabolism, longevity, and stress response. During acute selenium toxicity, TRXR-1 is not needed for survival. Instead, cells defend against adverse effects by using the HIF-1 pathway. Reactive oxygen species (ROS) and hydrogen sulfide (H₂S) inhibit the prolyl hydroxylase EGL-9 in high-selenium conditions, stabilizing HIF-1 and initiating a transcriptional detoxification process independent of the selenoprotein mechanism. Finally, this review also discuss selective neurotoxicity, a condition in which degeneration that occurs solely in cholinergic ventral cord motor neurons plays a distinctive and precarious role among trace elements.

Currently, no generalizable tools exist for predicting the impact of interventions on aging using gene expression changes. Here, we build a model for predicting potential geroprotectors by deconstructing the aging transcriptome into coexpression modules and identifying those modulated by life span–extending interventions in Caenorhabditis elegans ( C. elegans ). Many of these modules exhibited adaptive changes during aging that are linked to longevity. Using these longevity-associated modules, we predicted and validated 10 compounds (7 previously unreported) that significantly extended life span in C. elegans . RNA sequencing analysis of two top candidates also showed targeted modulation of our longevity-associated modules. We identified conservation of several modules in mice that were also correlated with frailty. Together, our findings demonstrate that beneficial transcriptomic adaptations occur during aging and that targeting longevity-associated modules offers a framework for geroprotector discovery.