BackgroundTemperature affects virtually all cellular processes. A quick increase in temperature challenges the cells to undergo a heat shock response to maintain cellular homeostasis. Heat shock factor-1 (HSF-1) functions as a major player in this response as it activates the transcription of genes coding for molecular chaperones (also called heat shock proteins) that maintain structural integrity of proteins. However, the mechanisms by which HSF-1 adjusts fundamental cellular processes such as growth, proliferation, differentiation and aging to the ambient temperature remain largely unknown.ResultsWe demonstrate here that in Caenorhabditis elegans HSF-1 represses the expression of daf-7 encoding a TGF-β (transforming growth factor-beta) ligand, to induce young larvae to enter the dauer stage, a developmentally arrested, non-feeding, highly stress-resistant, long-lived larval form triggered by crowding and starvation. Under favorable conditions, HSF-1 is inhibited by crowding pheromone-sensitive guanylate cyclase/cGMP (cyclic guanosine monophosphate) and systemic nutrient-sensing insulin/IGF-1 (insulin-like growth factor-1) signaling; loss of HSF-1 activity allows DAF-7 to promote reproductive growth. Thus, HSF-1 interconnects the insulin/IGF-1, TGF-β and cGMP neuroendocrine systems to control development and longevity in response to diverse environmental stimuli. Furthermore, HSF-1 upregulates another TGF-β pathway-interacting gene, daf-9/cytochrome P450, thereby fine-tuning the decision between normal growth and dauer formation.ConclusionTogether, these results provide mechanistic insight into how temperature, nutrient availability and population density coordinately influence development, lifespan, behavior and stress response through HSF-1.

Posttranslational modifications are ubiquitous regulators of cellular processes. The regulatory role of SUMOylation, the attachment of a small ubiquitin-related modifier to a target protein, has been implicated in fundamental processes like cell division, DNA damage repair, mitochondrial homeostasis, and stress responses. Recently, it is gaining more attention in drug discovery as well. As life expectancy keeps rising, more individuals are at risk for developing age-associated diseases. This not only makes a person’s life uncomfortable, but it also places an economic burden on society. Therefore, finding treatments for age-related diseases is an important issue. Understanding the basic mechanisms in the cell under normal and disease conditions is fundamental for drug discovery. There is an increasing number of reports showing that the ageing process could be influenced by SUMOylation. Similarly, SUMOylation is essential for proper neuronal function. In this review we summarize the latest results regarding the connection between SUMOylation and neurodegenerative diseases. We highlight the significance of specific SUMO target proteins and the importance of SUMO isoform specificity.

SummaryAging is accompanied by a pervasive collapse of proteostasis, while reducing general protein synthesis promotes longevity across taxa. Here, we show that the eIF4E isoform IFE-2 is increasingly sequestered in mRNA processing (P) bodies during aging and upon stress in Caenorhabditis elegans. Loss of the enhancer of mRNA decapping EDC-3 causes further entrapment of IFE-2 in P bodies and lowers protein synthesis rates in somatic tissues. Animals lacking EDC-3 are long lived and stress resistant, congruent with IFE-2-deficient mutants. Notably, neuron-specific expression of EDC-3 is sufficient to reverse lifespan extension, while sequestration of IFE-2 in neuronal P bodies counteracts age-related neuronal decline. The effects of mRNA decapping deficiency on stress resistance and longevity are orchestrated by a multimodal stress response involving the transcription factor SKN-1, which mediates lifespan extension upon reduced protein synthesis. Our findings elucidate a mechanism of proteostasis control during aging through P body-mediated regulation of protein synthesis in the soma.

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Mitochondria are critical to tissues and organs characterized by high-energy demands, such as the nervous system. They provide essential energy and metabolites, and maintain Ca2+ balance, which is imperative for proper neuronal function and development. Emerging findings further underline the role of mitochondria in neurons. Technical advances in the last decades made it possible to investigate key mechanisms in neuronal development and the contribution of mitochondria therein. In this article, we discuss the latest findings relevant to the involvement of mitochondria in neuronal development, placing emphasis on mitochondrial metabolism and dynamics. In addition, we survey the role of mitochondrial energy metabolism and Ca2+ homeostasis in proper neuronal function, and the involvement of mitochondria in axon myelination.

The insulin/IGF signalling pathway impacts lifespan across distant taxa, by controlling the activity of nodal transcription factors. In the nematode Caenorhabditis elegans, the transcription regulators DAF-16/FOXO and SKN-1/Nrf function to promote longevity under conditions of low insulin/IGF signalling and stress. The activity and subcellular localization of both DAF-16 and SKN-1 is further modulated by specific posttranslational modifications, such as phosphorylation and ubiquitination. Here, we show that ageing elicits a marked increase of SUMO levels in C. elegans. In turn, SUMO fine-tunes DAF-16 and SKN-1 activity in specific C. elegans somatic tissues, to enhance stress resistance. SUMOylation of DAF-16 modulates mitochondrial homeostasis by interfering with mitochondrial dynamics and mitophagy. Our findings reveal that SUMO is an important determinant of lifespan, and provide novel insight, relevant to the complexity of the signalling mechanisms that influence gene expression to govern organismal survival in metazoans.

Aging is the major risk factor for several life‐threatening pathologies and impairs the function of multiple cellular compartments and organelles. Age‐dependent deterioration of nuclear morphology is a common feature in evolutionarily divergent organisms. Lipid droplets have been shown to localize in most nuclear compartments, where they impinge on genome architecture and integrity. However, the significance of progressive nuclear lipid accumulation and its impact on organismal homeostasis remain obscure. Here, we implement non‐linear imaging modalities to monitor and quantify age‐dependent nuclear lipid deposition in Caenorhabditis elegans. We find that lipid droplets increasingly accumulate in the nuclear envelope, during aging. Longevity‐promoting interventions, such as low insulin signaling and caloric restriction, abolish the rate of nuclear lipid accrual and decrease the size of lipid droplets. Suppression of lipotoxic lipid accumulation in hypodermal and intestinal nuclei is dependent on the transcription factor HLH‐30/TFEB and the triglyceride lipase ATGL‐1. HLH‐30 regulates the expression of ATGL‐1 to reduce nuclear lipid droplet abundance in response to lifespan‐extending conditions. Notably, ATGL‐1 localizes to the nuclear envelope and moderates lipid content in long‐lived mutant nematodes during aging. Our findings indicate that the reduced ATGL‐1 activity leads to excessive nuclear lipid accumulation, perturbing nuclear homeostasis and undermining organismal physiology, during aging.