Longevity is determined by ETS transcription factors in multiple tissues and diverse species.

Ageing populations pose one of the main public health crises of our time. Reprogramming gene expression by altering the activities of sequence-specific transcription factors (TFs) can ameliorate deleterious effects of age. Here we explore how a circuit of TFs coordinates pro-longevity transcriptional outcomes, which reveals a multi-tissue and multi-species role for an entire protein family: the E-twenty-six (ETS) TFs. In Drosophila, reduced insulin/IGF signalling (IIS) extends lifespan by coordinating activation of Aop, an ETS transcriptional repressor, and Foxo, a Forkhead transcriptional activator. Aop and Foxo bind the same genomic loci, and we show that, individually, they effect similar transcriptional programmes in vivo. In combination, Aop can both moderate or synergise with Foxo, dependent on promoter context. Moreover, Foxo and Aop oppose the gene-regulatory activity of Pnt, an ETS transcriptional activator. Directly knocking down Pnt recapitulates aspects of the Aop/Foxo transcriptional programme and is sufficient to extend lifespan. The lifespan-limiting role of Pnt appears to be balanced by a requirement for metabolic regulation in young flies, in which the Aop-Pnt-Foxo circuit determines expression of metabolic genes, and Pnt regulates lipolysis and responses to nutrient stress. Molecular functions are often conserved amongst ETS TFs, prompting us to examine whether other Drosophila ETS-coding genes may also affect ageing. We show that five out of eight Drosophila ETS TFs play a role in fly ageing, acting from a range of organs and cells including the intestine, adipose and neurons. We expand the repertoire of lifespan-limiting ETS TFs in C. elegans, confirming their conserved function in ageing and revealing that the roles of ETS TFs in physiology and lifespan are conserved throughout the family, both within and between species.

Xbp1 targets canonical UPRER and non-canonical pathways in separate tissues to promote longevity.

Transcription factors can reprogram gene expression to promote longevity. Here, we investigate the role of Drosophila Xbp1. Xbp1 is activated by splicing of its primary transcript, Xbp1u, to generate Xbp1s, a key activator of the endoplasmic reticulum unfolded protein response (UPRER). We show that Xbp1s induces the conical UPRER in the gut, promoting longevity from the resident stem cells. In contrast, in the fat body, Xbp1s does not appear to trigger UPRER but alters metabolic gene expression and is still able to extend lifespan. In the fat body, Xbp1s and dFOXO impinge on the same target genes, including the PGC-1α orthologue Srl, and dfoxo requires Xbp1 to extend lifespan. Interestingly, unspliceable version of the Xbp1 mRNA, Xbp1u can also extend lifespan, hinting at roles in longevity for the poorly characterized Xbp1u transcription factor. These findings reveal the diverse functions of Xbp1 in longevity in the fruit fly.

Transcriptional memory of dFOXO activation in youth curtails later-life mortality through chromatin remodeling and Xbp1.

A transient, homeostatic transcriptional response can result in transcriptional memory, programming subsequent transcriptional outputs. Transcriptional memory has great but unappreciated potential to alter animal aging as animals encounter a multitude of diverse stimuli throughout their lifespan. Here we show that activating an evolutionarily conserved, longevity-promoting transcription factor, dFOXO, solely in early adulthood of female fruit flies is sufficient to improve their subsequent health and survival in midlife and late life. This youth-restricted dFOXO activation causes persistent changes to chromatin landscape in the fat body and requires chromatin remodelers such as the SWI/SNF and ISWI complexes to program health and longevity. Chromatin remodeling is accompanied by a long-lasting transcriptional program that is distinct from that observed during acute dFOXO activation and includes induction of Xbp1. We show that this later-life induction of Xbp1 is sufficient to curtail later-life mortality. Our study demonstrates that transcriptional memory can profoundly alter how animals age.

Drug-eluting balloons with provisional bail-out or adjunctive stenting in de novo coronary artery lesions-a systematic review and meta-analysis.

BACKGROUND: Efficacy of drug-eluting balloons (DEB) for treatment of de novo coronary lesions remains controversial. The present systematic review and meta-analysis of randomised controlled trials assessed DEB with bare-metal stents (BMS) and also DEB with provisional bail-out stents ('DEB-only' strategy), to other conventional options: plain-old balloon angioplasty (POBA), BMS and drug-eluting stents (DES). METHODS: A systematic literature search from January 2000 until May 2017 was conducted. Primary outcome measure, late lumen loss (LLL); and secondary outcomes; binary restenosis, major adverse cardiac events (MACE), target lesion revascularization (TLR), myocardial infarction (MI), cardiovascular death and stent thrombosis were analysed. RESULTS: Seventeen RCTs were included with 2,616 patients. Several comparative groups showed significant differences. DEB with BMS were inferior to DES for LLL [mean difference (MD) =0.12 mm; 95% confidence interval (CI), 0.03 to 0.22; P=0.01]; and binary restenosis [risk ratio (RR) =1.89; (CI, 1.13 to 3.18); P=0.02]. DEB with BMS was superior to BMS for LLL [MD =-0.27 mm; (-0.45 to -0.10); P=0.002]; and MACE [RR =0.64; (0.46 to 0.90); P=0.010]. Finally, DEB alone was superior to POBA for LLL [MD =-0.39 mm; (-0.67 to -0.11); P=0.006] and binary restenosis [RR =0.20; (0.05 to 0.85); P=0.03] in bifurcation lesions. CONCLUSIONS: The results of this meta-analysis showed that whilst DEB with BMS is superior to BMS alone, the combination is inferior to DES for treatment of de novo coronary lesions. Thus, DEB + BMS should not be applied in de novo lesions unless in patients who have absolute contraindications to DES. DEB alone, however, should be considered for relative contraindications to DES such as small vessel disease and bifurcation lesions.

Raised plasma Robo4 and cardiac surgery-associated acute kidney injury.

OBJECTIVE: Endothelial dysfunction associated with systemic inflammation can contribute to organ injury/failure following cardiac surgery requiring cardiopulmonary bypass (CPB). Roundabout protein 4 (Robo4), an endothelial-expressed transmembrane receptor and regulator of cell activation, is an important inhibitor of endothelial hyper-permeability. We investigated the hypothesis that plasma levels of Robo4 are indicative of organ injury, in particular acute kidney injury (AKI), after cardiac surgery. METHODS: Patients (n = 32) undergoing elective cardiac surgery with CPB were enrolled, prospectively. Plasma Robo4 concentrations were measured pre-, 2 and 24 h post-operatively, using a commercially available ELISA. Plasma and endothelial markers of inflammation [interleukin (IL) -6, -8, -10: von Willibrand factor (vWF) and angiopoeitin-2 (Ang-2)] and the AKI marker, neutrophil gelatinase-associated lipocalin (NGAL), were also measured by ELISA. RESULTS: Plasma Robo4 increased significantly (p<0.001) from pre-operative levels of 2515 ± 904 pg/ml to 4473 ± 1915 pg/ml, 2 h after surgery; and returned to basal levels (2682 ± 979 pg/ml) by 24 h. Plasma cytokines, vWF and NGAL also increased 2 h post-operatively and remained elevated at 24 h. Ang-2 increased 24 h post-operatively, only. There was a positive, significant correlation (r = 0.385, p = 0.0298) between Robo-4 and IL-10, but not other cytokines, 2 h post-operatively. Whilst raised Robo4 did not correlate with indices of lung dysfunction or other biomarkers of endothelial activation; there was a positive, significant correlation between raised (2 h) plasma NGAL and Robo4 (r = 0.4322, p = 0.0135). When patients were classed as AKI or non-AKI either using NGAL cut-off of 150 ng/ml, or the AKI Network (AKIN) clinical classification; plasma Robo4 was significantly higher (p = 0.0073 and 0.003, respectively) in AKI vs. non-AKI patients (NGAL cut-off: 5350 ± 2191 ng/ml, n = 16 vs. 3595 ± 1068 pg/ml, n = 16; AKIN: 6546 pg/ml, IQR 5025-8079, n = 6; vs. 3727 pg/ml, IQR 1962-3727, n = 26) subjects. CONCLUSION: Plasma Robo4 levels are increased, transiently, following cardiac surgery requiring CPB; and higher levels in patients with AKI suggest a link between endothelial dysregulation and onset of AKI.