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Here, we provide a brief review of the mechanistic connections between immunity and aging-a fundamental biological relationship that remains poorly understood-by considering two intertwined questions: how does aging affect immunity, and how does immunity affect aging? On the one hand, aging contributes to the deterioration of immune function and predisposes the organism to infections (\"immuno-senescence\"). On the other hand, excessive activation of the immune system can accelerate degenerative processes, cause inflammation and immunopathology, and thus promote aging (\"inflammaging\"). Interestingly, several recent lines of evidence support the hypothesis that restrained or curbed immune activity at old age (that is, optimized age-dependent immune homeostasis) might actually improve realized immune function and thereby promote longevity. We focus mainly on insights from Drosophila, a powerful genetic model system in which both immunity and aging have been extensively studied, and conclude by outlining several unresolved questions in the field.

Animals with lifelong growth adjust their growth rates to nutrient availability, yet the underlying cellular and molecular mechanisms remain poorly understood. Here, we studied how food supply and TOR signaling regulate the cell cycle in a multipotent population of Vasa2-/Piwi1-expressing cells in the sea anemone Nematostella vectensis . We discovered that starvation induces a reversible G 1 /G 0 cell cycle arrest in Vasa2+/Piwi1+ cells and that cell cycle re-entry upon refeeding is dependent on TOR signaling. In addition, the length of the refeeding stimulus after starvation determines the proportion of cells that re-enter S-phase. Remarkably, prolonged starvation delayed both refeeding-induced TOR signaling activation and S-phase re-entry, and led to a global decrease in the active histone mark H3K27ac in Vasa2+/Piwi1+ cells. This strongly suggests that Nematostella Vasa2+/Piwi1+ cells undergo starvation-controlled quiescence deepening, a phenomenon previously described only in unicellular eukaryotes and mammalian cell culture. The nutritional control of quiescence and cell proliferation may thus be a fundamental, evolutionarily conserved strategy underlying the environmental regulation of indeterminate growth in animals.

Much has been learned about the genetics of aging from studies in model organisms, but still little is known about naturally occurring alleles that contribute to variation in longevity. For example, analysis of mutants and transgenes has identified insulin signaling as a major regulator of longevity, yet whether standing variation in this pathway underlies microevolutionary changes in lifespan and correlated fitness traits remains largely unclear. Here, we have analyzed the genomes of a set of Drosophila melanogaster lines that have been maintained under direct selection for postponed reproduction and indirect selection for longevity, relative to unselected control lines, for over 35 years. We identified many candidate loci shaped by selection for longevity and late‐life fertility, but – contrary to expectation – we did not find overrepresentation of canonical longevity genes. Instead, we found an enrichment of immunity genes, particularly in the Toll pathway, suggesting that evolutionary changes in immune function might underpin – in part – the evolution of late‐life fertility and longevity. To test whether this genomic signature is causative, we performed functional experiments. In contrast to control flies, long‐lived flies tended to downregulate the expression of antimicrobial peptides upon infection with age yet survived fungal, bacterial, and viral infections significantly better, consistent with alleviated immunosenescence. To examine whether genes of the Toll pathway directly affect longevity, we employed conditional knockdown using in vivo RNAi. In adults, RNAi against the Toll receptor extended lifespan, whereas silencing the pathway antagonist cactus‐–causing immune hyperactivation – dramatically shortened lifespan. Together, our results suggest that genetic changes in the age‐dependent regulation of immune homeostasis might contribute to the evolution of longer life.

Background The detection of de novo synthesized mRNA transcripts is crucial for understanding the regulation of eukaryotic transcription. Using nucleoside or nucleotide analogues to label nascent RNA is potentially jeopardized by the ubiquitous presence of ribonucleotide reductase enzymes (RNRs) that can convert ribonucleotides into 2’-deoxyribonucleotides, the building blocks of DNA. Despite this challenge, the uridine analogue 5-ethynyl uridine (EU) has been commercialized and routinely used as specific label for nascent RNAs. Here, we employ confocal imaging, flow cytometry and biochemistry methods to study the specificity of EU to label RNA in six different animal species. Results We demonstrate that EU integrates as expected predominantly into RNA of human embryonic kidney cell line (HEK293T), the Drosophila wing disc and the comb jelly Mnemiopsis leidyi . In contrast, we found that EU predominantly labels DNA in the sea anemones Nematostella vectensis and Exaiptasia diaphana , and the polychaete Platynereis dumerilii . In Nematostella , we show that inhibiting RNR by hydroxyurea abolishes cell proliferation and the incorporation of EU into DNA. Alternative compounds for labelling nascent RNA, such as 5-ethynyl cytidine (EC), 5-ethynyl uridine triphosphate (EUTP) or 2-ethynyl adenosine (EA) show similarly low specificity for RNA in Nematostella . Conclusions Our findings raise concerns about the specificity of ethynylated nucleosides and nucleotides, including EU, to label RNA in some animals. We therefore suggest good practice guidelines help identifying unintentional DNA labelling when using EU to label nascent RNA.

Mechanisms that ensure and maintain the stability of genetic information are fundamentally important for organismal function and can have a large impact on disease, aging, and life span. While a multi-layered cellular apparatus exists to detect and respond to DNA damage, various insults from environmental and endogenous sources continuously affect DNA integrity. Over time this can lead to the accumulation of somatic mutations, which is thought to be one of the major causes of aging. We have previously found that overexpression of the essential human DNA repair and splicing factor SNEV, also called PRP19 or hPso4, extends replicative life span of cultured human endothelial cells and impedes accumulation of DNA damage. Here, we show that adult-specific overexpression of dPrp19 , the D. melanogaster ortholog of human SNEV/PRP19/hPso4, robustly extends life span in female fruit flies. This increase in life span is accompanied by reduced levels of DNA damage and improved resistance to oxidative and genotoxic stress. Our findings suggest that dPrp19 plays an evolutionarily conserved role in aging, life span modulation and stress resistance, and support the notion that superior DNA maintenance is key to longevity. Aging: Living longer by improving DNA repair Increasing levels of DNA repair factor Prp19 in fruit flies extends their life span and protects against stress. Prp19 is a protein that is present in a wide range of organisms and enables human endothelial cells to live longer in vitro. In this article, an international team of scientists from Austria, Germany and Switzerland found that higher Prp19 levels also prolong the life span of a whole organism in fruit flies, reduce DNA damage and increase survival when exposed to DNA damaging compounds. In contrast to female flies, males were unaffected. Their findings support the long-held view that repair of DNA damage, one of the hallmarks of aging, is key to longevity. They also provide an intriguing but poorly understood connection between cellular aging and the survival of whole organisms.

Correction to: npj Aging and Mechanisms of Disease, advance online publication, 15 March 2017; doi:10.1038/s41514-017-0005-z

Animals with lifelong growth adjust their growth rates to nutrient availability, yet the underlying cellular and molecular mechanisms remain poorly understood. Here, we studied how food supply and TOR signalling regulate the cell cycle in a multipotent, Vasa2-/Piwi1-expressing cell population in the sea anemone Nematostella vectensis. We discovered that starvation induces a reversible G1/G0 cell cycle arrest in Vasa2+/Piwi1+ cells and that cell cycle re-entry upon refeeding is dependent on TOR signalling. In addition, the length of the refeeding stimulus after starvation determines the proportion of cells that re-enter S-phase. Remarkably, prolonged starvation delayed both refeeding-induced TOR signalling activation and S-phase re-entry. This strongly suggests that Nematostella Vasa2+/Piwi1+ cells undergo starvation-controlled quiescence deepening, previously described only in unicellular eukaryotes and mammalian cell culture. The nutritional control of quiescence and cell proliferation may thus be a fundamental, evolutionarily conserved strategy underlying the environmental regulation of indeterminate growth in animals.Competing Interest StatementThe authors have declared no competing interest.Footnotes* https://figshare.com/projects/Flow_cytometry_files_Starvation_duration_regulates_cellular_quiescence_depth_and_cell_cycle_re-entry_in_a_sea_anemone/234587* https://data.mendeley.com/preview/82g2scj6c7?a=16e5b043-9ff3-4f9b-97bc-7f0677839a7a

The detection of de novo synthesized mRNA transcripts is crucial for understanding the regulation of eukaryotic transcription. Using nucleoside or nucleotide analogues to label nascent RNA is potentially jeopardized by the ubiquitous presence of ribonucleotide reductase enzymes (RNRs) that can convert ribonucleotides into 2’-deoxyribonucleotides, the building blocks of DNA. Despite this challenge, the uridine analogue 5-ethynyl uridine (EU) has been commercialized and routinely used as specific label for nascent RNAs. Here, we employ confocal imaging, flow cytometry and biochemistry methods to study the specificity of EU to label RNA in six different animal species. We demonstrate that EU integrates as expected predominantly into RNA of human embryonic kidney cell line (HEK293), the Drosophila wing disc and the comb jelly Mnemiopsis leidyi. In contrast, we found that EU predominantly labels DNA in the sea anemones Nematostella vectensis and Exaiptasia diaphana, and the polychaete Platynereis dumerilii. In Nematostella, we show that inhibiting RNR by hydroxyurea abolishes cell proliferation and the incorporation of EU into DNA. Alternative compounds for labelling nascent RNA, such as 5-ethynyl cytidine (EC), 5-ethynyl uridine triphosphate (EUTP) or 2-ethynyl adenosine (EA) show similarly low specificity for RNA in Nematostella. Our findings raise concerns about the specificity of ethynylated nucleosides and nucleotides, including EU, to label RNA in some animals. We therefore suggest good practice guidelines for using EU as an RNA labelling tool and discuss pitfalls and indicators that help identifying unintentional DNA labelling.

Animals with indeterminate growth can adapt their growth rate and body size to changing food availability throughout their lifetime. As the cellular basis underlying food-dependent growth plasticity is poorly understood, we quantified how the sea anemones Nematostella vectensis and Exaiptasia diaphana (Aiptasia) respond to feeding and starvation on organismal and cellular levels. Using mathematical modelling to analyse growth phases, we found that growth and shrinkage rates in Nematostella are exponential, stereotypic and accompanied by high levels of cell gain or loss, respectively. During starvation and re-feeding, a considerable proportion of juvenile polyp cells (>7%) reversibly shift between S/G2/M and G1/G0 cell cycle phases, suggesting a tight nutritional control of quiescence and cell cycle re-entry. In the facultative symbiotic sea anemone Aiptasia, we found that growth and cell proliferation rates are dependent on the symbiotic state and, in comparison to Nematostella, respond less strongly to changes in food supply. Altogether, we provide a benchmark and resource to study the nutritional regulation of body plasticity on molecular, cellular and genomic levels using the rich functional toolkit available for Nematostella. Feeding and starvation in sea anemones induce growth and shrinkage, cell size changes and dynamic cell proliferation changes that support a nutritional control of quiescence and cell cycle re-entry.