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Summary The mitochondrial unfolded protein response (UPRmt) is a promising pharmacological target for aging and age-related diseases. However, the integrative analysis of the impact of UPRmt activation on different signaling layers in animals with different genetic backgrounds is lacking. Here, we applied systems approaches to investigate the effect of UPRmt induced by doxycycline (Dox) on transcriptome, proteome, and lipidome in two genetically divergent worm strains, named N2 and CB4856. From the integrated omics datasets, we found that Dox prolongs lifespan of both worm strains through shared and strain-specific mechanisms. Specifically, Dox strongly impacts mitochondria, upregulates defense response, and lipid metabolism, while decreasing triglycerides. We further validated that lipid genes acs-2/20 and fat-7/6 were required for Dox-induced UPRmt and longevity in N2 and CB4856 worms, respectively. Our data have translational value as they indicate that the beneficial effects of Dox-induced UPRmt on lifespan are consistent across different genetic backgrounds through different regulators., Graphical abstract, Highlights • Dox extends lifespan of N2 and CB4856 via shared and strain-specific mechanisms • Dox controls mitochondria, defense responses, and lipid metabolism in both strains • Dox-mediated longevity requires acs-2/20 in N2 and fat-7/6 in CB4856 worms, Chronobiology; Proteomics; Transcriptomics

Transcriptome‐based drug screening is emerging as a powerful tool to identify geroprotective compounds to intervene in age‐related disease. We hypothesized that, by mimicking the transcriptional signature of the highly conserved longevity intervention of FOXO3 (daf‐16 in worms) overexpression, we could identify and repurpose compounds with similar downstream effects to increase longevity. Our in silico screen, utilizing the LINCS transcriptome database of genetic and compound interventions, identified several FDA‐approved compounds that activate FOXO downstream targets in mammalian cells. These included the neuromuscular blocker atracurium, which also robustly extends both lifespan and healthspan in Caenorhabditis elegans. This longevity is dependent on both daf‐16 signaling and inhibition of the neuromuscular acetylcholine receptor subunit unc‐38. We found unc‐38 RNAi to improve healthspan, lifespan, and stimulate DAF‐16 nuclear localization, similar to atracurium treatment. Finally, using RNA‐seq transcriptomics, we identify atracurium activation of DAF‐16 downstream effectors. Together, these data demonstrate the capacity to mimic genetic lifespan interventions with drugs, and in doing so, reveal that the neuromuscular acetylcholine receptor regulates the highly conserved FOXO/DAF‐16 longevity pathway., Transcriptome‐based drug screening is a powerful tool to identify geroprotective compounds. By mimicking the transcriptional signature of FOXO3 (daf‐16 in worms) overexpression, we identified the neuromuscular blocker atracurium, which extends both lifespan and healthspan in Caenorhabditis elegans. Here we demonstrate the capacity to mimic genetic lifespan interventions with drugs, and reveal that the neuromuscular acetylcholine receptor regulates the highly conserved DAF‐16 longevity pathway.

The mitochondrial unfolded protein response (UPRmt) is a promising pharmacological target for aging and age-related diseases. However, the integrative analysis of the impact of UPRmt activation on different layers of signaling in animals with a different genetic background is lacking. In this study, we applied systems approaches to investigate the effect of UPRmt induced by administering doxycycline (Dox) on transcriptome, proteome, lipidome, and metabolome in two genetically divergent C. elegans strains. We found that Dox prolongs lifespan of both worm strains through pathways in both shared and strain-specific manners. From the integrated omics datasets, we observed a strong impact of Dox on mitochondrial functions, detected upregulated defense response and lipid metabolism, identified decreased triglycerides and lowered metabolome profiles in both strains. This conserved phenomic footprint has great translational value as it indicates that the beneficial effects of Dox-induced UPRmt on health and lifespan are consistent across different genetic backgrounds.

Comprehensive metabolomic and lipidomic mass spectrometry methods are in increasing demand; for instance, in research related to nutrition and aging. The nematode Caenorhabditis elegans is a key model organism in these fields, owing to the large repository of available C. elegans mutants and their convenient natural lifespan. Here, we describe a robust and sensitive analytical method for the semi-quantitative analysis of >100 polar (metabolomics) and >1000 apolar (lipidomics) metabolites in C. elegans, using a single-sample preparation. Our method is capable of reliably detecting a wide variety of biologically relevant metabolic aberrations in, for example, glycolysis and the tricarboxylic acid cycle, pyrimidine metabolism and complex lipid biosynthesis. In conclusion, we provide a powerful analytical tool that maximizes metabolic data yield from a single sample. This article has an associated First Person interview with the joint first authors of the paper., Summary: We describe an integrated metabolomics and lipidomics method for analyzing metabolites in C. elegans using a single-sample preparation, which provides a robust way of obtaining comprehensive, high-quality metabolic data from biological samples.

Since the identification and definition of the hallmarks of aging, these aspects of molecular and cellular decline have been most often described as isolated or distinct mechanisms. However, there is significant evidence demonstrating interplay between most of these hallmarks and that they have the capacity to influence and regulate one another. These interactions are demonstrable across the tree of life, yet not all aspects are conserved. Here, we describe an integrative view on the hallmarks of aging by using the hallmark “mitochondrial dysfunction” as a focus point, and illustrate its capacity to both influence and be influenced by the other hallmarks of aging. We discuss the effects of mitochondrial pathways involved in aging, such as oxidative phosphorylation, mitochondrial dynamics, mitochondrial protein synthesis, mitophagy, reactive oxygen species and mitochondrial DNA damage in relation to each of the primary, antagonistic and integrative hallmarks. We discuss the similarities and differences in these interactions throughout the tree of life, and speculate how speciation may play a role in the variation in these mechanisms. We propose that the hallmarks are critically intertwined, and that mapping the full extent of these interactions would be of significant benefit to the aging research community.

Comprehensive metabolomic and lipidomic mass spectrometry methods are in increasing demand, for instance in research related to nutrition and aging. The nematode C. elegans is a key model organism in these fields, due to the large repository of available C. elegans mutants and their convenient natural lifespan. Here, we describe a robust and sensitive analytical method for the semi-quantitative analysis of >100 polar (metabolomics) and >1000 apolar (lipidomics) metabolites in C. elegans, using a single sample preparation. Our method is capable of reliably detecting a wide variety of biologically relevant metabolic aberrations in, for instance, glycolysis and the TCA cycle, pyrimidine metabolism and complex lipid biosynthesis. In conclusion, we provide a powerful analytical tool that maximizes metabolic data yield from a single sample.Graphical abstract

Lifespan in eukaryotic species can be prolonged by shifting from cellular states favouring growth to those favouring maintenance and stress resistance. For instance, perturbations in mitochondrial oxidative phosphorylation (OXPHOS) can shift cells into this latter state and extend lifespan. Because mitochondria rely on proteins synthesized from nuclear as well as mitochondrial DNA, they need to constantly send and receive messages from other compartments of the cell in order to function properly and maintain homeostasis, and lifespan extension is often dependent on this cross-compartmental signalling. Here, we describe the mechanisms of bi-directional mitochondrial cross-compartmental signalling resulting in proteostasis and longevity. These proteostasis mechanisms are highly context-dependent, governed by the origin and extent of stress. Furthermore, we discuss the translatability of these mechanisms and explore therapeutic developments, such as the antibiotic studies targeting mitochondria or mitochondria-derived peptides as therapies for age-related diseases such as neurodegeneration and cancer.This article is part of the theme issue ‘Retrograde signalling from endosymbiotic organelles’.

Aging is emerging as a druggable target with growing interest from academia, industry and investors. New technologies such as artificial intelligence and advanced screening techniques, as well as a strong influence from the industry sector may lead to novel discoveries to treat age-related diseases. The present review summarizes presentations from the 7th Annual Aging Research and Drug Discovery (ARDD) meeting, held online on the 1st to 4th of September 2020. The meeting covered topics related to new methodologies to study aging, knowledge about basic mechanisms of longevity, latest interventional strategies to target the aging process as well as discussions about the impact of aging research on society and economy. More than 2000 participants and 65 speakers joined the meeting and we already look forward to an even larger meeting next year. Please mark your calendars for the 8th ARDD meeting that is scheduled for the 31st of August to 3rd of September, 2021, at Columbia University, USA., Aging, 12 (24), ISSN:1945-4589

Reversing or slowing the aging process brings great promise to treat or prevent age‐related disease, and targeting the hallmarks of aging is a strategy to achieve this. Epigenetics affects several if not all of the hallmarks of aging and has therefore emerged as a central target for intervention. One component of epigenetic regulation involves histone deacetylases (HDAC), which include the “classical” histone deacetylases (of class I, II, and IV) and sirtuin deacetylases (of class III). While targeting sirtuins for healthy aging has been extensively reviewed elsewhere, this review focuses on pharmacologically inhibiting the classical HDACs to promote health and longevity. We describe the theories of how classical HDAC inhibitors may operate to increase lifespan, supported by studies in model organisms. Furthermore, we explore potential mechanisms of how HDAC inhibitors may have such a strong grasp on health and longevity, summarizing their links to other hallmarks of aging. Finally, we show the wide range of age‐related preclinical disease models, ranging from neurodegeneration to heart disease, diabetes to sarcopenia, which show improvement upon HDAC inhibition.

The deregulation of metabolism is a hallmark of aging. As such, changes in the expression of metabolic genes and the profiles of amino acid levels are features associated with aging animals. We previously reported that the levels of most amino acids decline with age in Caenorhabditis elegans (C. elegans). Glycine, in contrast, substantially accumulates in aging C. elegans. In this study we show that this is coupled to a decrease in gene expression of enzymes important for glycine catabolism. We further show that supplementation of glycine significantly prolongs C. elegans lifespan, and early adulthood is important for its salutary effects. Moreover, supplementation of glycine ameliorates specific transcriptional changes that are associated with aging. Glycine feeds into the methionine cycle. We find that mutations in components of this cycle, methionine synthase (metr-1) and S-adenosylmethionine synthetase (sams-1), completely abrogate glycine-induced lifespan extension. Strikingly, the beneficial effects of glycine supplementation are conserved when we supplement with serine, which also feeds into the methionine cycle. RNA-sequencing reveals a similar transcriptional landscape in serine- and glycine-supplemented worms both demarked by widespread gene repression. Taken together, these data uncover a novel role of glycine in the deceleration of aging through its function in the methionine cycle., Author summary There is a growing number of studies showing that amino acids function as signal metabolites that influence aging and health. Although contemporary -OMICs studies have uncovered various associations between metabolite levels and aging, in many cases the directionality of the relationships is unclear. In a recent metabolomics study, we found that glycine accumulates in aged C. elegans while other amino acids decrease. The present study shows that glycine supplementation increases lifespan and drives a genome-wide inhibition effect on C. elegans gene expression. Glycine as a one-carbon donor fuels the methyl pool of one-carbon metabolism composed of the folate and methionine cycles. We find that the glycine-mediated longevity effect is fully dependent on the methionine cycle, and that all of our observations are conserved with supplementation of the other one-carbon amino acid, serine. These results provide a novel role for glycine as a promoter of longevity and bring new insight into the role of one-carbon amino acids in the regulation of aging that may ultimately be beneficial for humans.

Cell Metabolism, 31 (3), ISSN:1550-4131, ISSN:1932-7420

Mutations in theclk-1gene impair mitochondrial ubiquinone biosynthesis and extend the lifespan ofC. elegans.We demonstrate here that this life extension is linked to the repression of cytoplasmic protein translation.Clk-1mutations inhibit polyribosome formation similarly todaf-2mutations that dampen insulin signaling. Comparisons of total versus polysomal RNAs inclk-1mutants reveal a reduction in the translational efficiencies of mRNAs coding for elements of the translation machinery and an increase in those coding for the oxidative phosphorylation and autophagy pathways. Knocking down the transcription initiation factor TAF-4, a protein that becomes sequestered in the cytoplasm during early embryogenesis to induce transcriptional silencing, ameliorates theclk-1inhibition of polyribosome formation. These results underscore a prominent role for the repression of cytoplasmic protein translation in eukaryotic lifespan extension, and suggest that mutations impairing mitochondrial function are able to exploit this repression similarly to reductions of insulin signaling. Moreover, this report reveals an unexpected role for TAF-4 as a repressor of polyribosome formation when ubiquinone biosynthesis is compromised.

Mutations in theclk-1gene impair mitochondrial ubiquinone biosynthesis and extend the lifespan inCaenorhabditis elegans. We demonstrate here that this life extension is linked to the repression of cytoplasmic mRNA translation, independent of the alleged nuclear form of CLK-1.Clk-1mutations inhibit polyribosome formation similarly todaf-2mutations that dampen insulin signaling. Comparisons of total versus polysomal RNAs inclk-1(qm30)mutants reveal a reduction in the translational efficiencies of mRNAs coding for elements of the translation machinery and an increase in those coding for the oxidative phosphorylation and autophagy pathways. Knocking down the transcription initiation factor TATA-binding protein-associated factor 4, a protein that becomes sequestered in the cytoplasm during early embryogenesis to induce transcriptional silencing, ameliorates theclk-1inhibition of polyribosome formation. These results underscore a prominent role for the repression of cytoplasmic protein synthesis in eukaryotic lifespan extension and suggest that mutations impairing mitochondrial function are able to exploit this repression similarly to reductions of insulin signaling. Moreover, this report reveals an unexpected role for TATA-binding protein-associated factor 4 as a repressor of polyribosome formation when ubiquinone biosynthesis is compromised.