Caenorhabditis elegans is an exceptionally valuable model for aging research because of many advantages, including its genetic tractability, short lifespan, and clear age‐dependent physiological changes. Aged C. elegans display a decline in their anatomical and functional features, including tissue integrity, motility, learning and memory, and immunity. Caenorhabditis elegans also exhibit many age‐associated changes in the expression of microRNAs and stress‐responsive genes and in RNA and protein quality control systems. Many of these age‐associated changes provide information on the health of the animals and serve as valuable biomarkers for aging research. Here, we review the age‐dependent changes in C. elegans and their utility as aging biomarkers indicative of the physiological status of aging.

Excessive glucose causes various diseases and decreases lifespan by altering metabolic processes, but underlying mechanisms remain incompletely understood. Here, we show that Lipin 1/LPIN‐1, a phosphatidic acid phosphatase and a putative transcriptional coregulator, prevents life‐shortening effects of dietary glucose on Caenorhabditis elegans. We found that depletion of lpin‐1 decreased overall lipid levels, despite increasing the expression of genes that promote fat synthesis and desaturation, and downregulation of lipolysis. We then showed that knockdown of lpin‐1 altered the composition of various fatty acids in the opposite direction of dietary glucose. In particular, the levels of two ω‐6 polyunsaturated fatty acids (PUFAs), linoleic acid and arachidonic acid, were increased by knockdown of lpin‐1 but decreased by glucose feeding. Importantly, these ω‐6 PUFAs attenuated the short lifespan of glucose‐fed lpin‐1‐inhibited animals. Thus, the production of ω‐6 PUFAs is crucial for protecting animals from living very short under glucose‐rich conditions.

A hallmark of aging is immunosenescence, a decline in immune functions, which appeared to be inevitable in living organisms, including Caenorhabditis elegans. Here, we show that genetic inhibition of the DAF-2/insulin/IGF-1 receptor drastically enhances immunocompetence in old age in C. elegans. We demonstrate that longevity-promoting DAF-16/FOXO and heat-shock transcription factor 1 (HSF-1) increase immunocompetence in old daf-2(−) animals. In contrast, p38 mitogen-activated protein kinase 1 (PMK-1), a key determinant of immunity, is only partially required for this rejuvenated immunity. The up-regulation of DAF-16/FOXO and HSF-1 decreases the expression of the zip-10/bZIP transcription factor, which in turn down-regulates INS-7, an agonistic insulin-like peptide, resulting in further reduction of insulin/IGF-1 signaling (IIS). Thus, reduced IIS prevents immune aging via the up-regulation of anti-aging transcription factors that modulate an endocrine insulin-like peptide through a feedforward mechanism. Because many functions of IIS are conserved across phyla, our study may lead to the development of strategies against immune aging in humans.

Mitochondria are crucial organelles that generate cellular energy and metabolites. Recent studies indicate that mitochondria also regulate immunity. In this review, we discuss key roles of mitochondria in immunity against pathogen infection and underlying mechanisms, focusing on discoveries using Caenorhabditis elegans. Various mitochondrial processes, including mitochondrial surveillance mechanisms, mitochondrial unfolded protein response (UPRmt), mitophagy, and reactive oxygen species (ROS) production, contribute to immune responses and resistance of C. elegans against pathogens. Biological processes of C. elegans are usually conserved across phyla. Thus, understanding the mechanisms of mitochondria-mediated defense responses in C. elegans may provide insights into similar mechanisms in complex organisms, including mammals.

Nonsense-mediated mRNA decay (NMD) is a biological surveillance mechanism that eliminates mRNA transcripts with premature termination codons. In Caenorhabditis elegans, NMD contributes to longevity by enhancing RNA quality. Here, we aimed at identifying NMD-modulating factors that are crucial for longevity in C. elegans by performing genetic screens. We showed that knocking down each of algn-2/asparagine-linked glycosylation protein, zip-1/bZIP transcription factor, and C44B11.1/FAS apoptotic inhibitory molecule increased the transcript levels of NMD targets. Among these, algn-2 exhibited an age-dependent decrease in its expression and was required for maintaining normal lifespan and for longevity caused by various genetic interventions. We further demonstrated that upregulation of ALGN-2 by inhibition of daf-2/insulin/IGF-1 receptor contributed to longevity in an NMD-dependent manner. Thus, algn-2, a positive regulator of NMD, plays a crucial role in longevity in C. elegans, likely by enhancing RNA surveillance. Our study will help understand how NMD-mediated mRNA quality control extends animal lifespan. INTRODUCTIONEukaryotic cells are equipped with mechanisms that maintain proper gene expression and prevent the production of deleterious proteins. Nonsense-mediated mRNA decay (NMD) is an mRNA quality control mechanism that monitors and degrades abnormal transcripts with premature termination codons (PTCs) (He and Jacobson, 2015;Kim and Maquat, 2019;Kurosaki et al., 2019). NMD targets also include mRNAs with long (>1 kb) 3 0 untranslated regions, upstream open reading frames, or selenocysteine-encoding UGA codons (He and Jacobson, 2015;Kim and Maquat, 2019;Kurosaki et al., 2019). Thus, NMD is crucial for RNA quality surveillance and the maintenance of the correct transcriptome in organisms. Key evolutionarily conserved components of NMD have been identified by using model organisms, including the budding yeast Saccharomyces cerevisiae and the nematode Caenorhabditis elegans. A genetic screen using C. elegans has identified the main NMD components, smg (suppressor with morphological effect on genitalia)-1 through smg-7 (Hodgkin et al., 1989;Mango, 2001). SMG-1 is a phosphatidylinositol 3-kinase-related kinase that phosphorylates SMG-2/UPF1 RNA helicase (Hodgkin et al., 1989;Mango, 2001). This event activates the NMD machinery and leads to the cleavage of target mRNAs via the endonuclease SMG-6 (