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Abstract Immunosenescence is an age-dependent decline in immune functions and hallmark of aging in diverse species, ranging from invertebrates to mammals. However, identifying the factors responsible for immunosenescence is challenging because of the complexity of immune systems and aging in mammals. The roundworm Caenorhabditis elegans is suitable for understanding immunosenescence because of its simple immune system and rapid aging process. In this review, we discuss the advances in our understanding of immunosenescence in C. elegans. PMK-1/p38 mitogen-activated protein kinase (MAPK), SKN-1/NRF, and ZIP-10/bZIP transcription factor regulate immunosenescence through p38 MAPK and insulin/IGF-1 signaling pathways. Because these factors and pathways are evolutionarily conserved, the findings discussed in this review may help understand the mechanisms underlying immunosenescence and develop new treatment therapy for immunosenescence in humans.

Hypomethylating agents (HMAs), such as azacitidine and decitabine, induce cancer cell death by demethylating DNAs to promote the expression of tumor-suppressor genes. HMAs also reactivate the transcription of endogenous double-stranded RNAs (dsRNAs) that trigger the innate immune response and subsequent apoptosis via viral mimicry. However, the expression patterns of endogenous dsRNAs and their relevance in the efficacy of HMAs remain largely uninvestigated. Here, we employ amidine-conjugated spiropyran (Am-SP) to examine the dynamic expression pattern of total dsRNAs regulated by HMAs. By analyzing the bone-marrow aspirates of myelodysplastic syndrome or acute myeloid leukemia patients who received the HMAs, we find a dramatic increase in total dsRNA levels upon treatment only in patients who later benefited from the therapy. We further apply our approach in solid tumor cell lines and show that the degree of dsRNA induction correlates with the effectiveness of decitabine in most cases. Notably, when dsRNA induction is accompanied by increased expression of nc886 RNA, decitabine becomes ineffective. Collectively, our study establishes the potential application of monitoring the total dsRNA levels by a small molecule as an analytical method and a dynamic marker to predict the clinical outcome of the HMA therapy.

Aging is accompanied by the gradual deregulation of the transcriptome. However, whether age-dependent changes in the transcriptome are evolutionarily conserved or diverged remains largely unexplored. Here, we performed a meta-analysis examining the age-dependent changes in the transcriptome using publicly available datasets of 11 representative metazoans, ranging from Caenorhabditis elegans to humans. To identify the transcriptomic changes associated with aging, we analyzed various aspects of the transcriptome, including genome composition, RNA processing, and functional consequences. The use of introns and novel splice sites tended to increase with age, particularly in the brain. In addition, our analysis suggests that the age-dependent accumulation of premature termination codon-containing transcripts is a common feature of aging across multiple animal species. Using C. elegans as a test model, we showed that several splicing factors that are evolutionarily conserved and age-dependently downregulated were required to maintain a normal lifespan. Thus, aberrant RNA processing appears to be associated with aging and a short lifespan in various species. [ABSTRACT FROM AUTHOR]

Aging is associated with functional and structural declines in organisms over time. Organisms as diverse as the nematode Caenorhabditis elegans and mammals share signaling pathways that regulate aging and lifespan. In this review, we discuss recent combinatorial approach to aging research employing C. elegans and mammalian systems that have contributed to our understanding of evolutionarily conserved aging-regulating pathways. The topics covered here include insulin/IGF-1, mechanistic target of rapamycin (mTOR), and sirtuin signaling pathways; dietary restriction; autophagy; mitochondria; and the nervous system. A combinatorial approach employing high-throughput, rapid C. elegans systems, and human model mammalian systems is likely to continue providing mechanistic insights into aging biology and will help develop therapeutics against age-associated disorders. [ABSTRACT FROM AUTHOR]