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Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response. Cellular pathways modulating longevity and stress resistance are known to affect protein translation. Here the authors show that the RNA methyltransferase, Nsun5, or its yeast homologue Rcm1, regulates lifespan of three different model organisms by modifying ribosomal RNA at a specific cytosine residue.

Nature Communications 6: Article number: 6158 (2015); Published: 30 January 2015; Updated: 11 May 2016 This Article contains an error in the numbering of the C. elegans 25S rRNA site methylated by nsun-5, which was incorrectly given as C3381. The correct methylation site is C2381. The correct version of Fig.

There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life- and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extract from the plant Solidago virgaurea subsp. alpestris, which exhibited weak senolytic activity, delayed the acquisition of a senescent phenotype and induced a papillary phenotype with improved functionality in human dermal fibroblasts. When administered to stress-induced premature senescent fibroblasts, this extract changed their global mRNA expression profile and particularly reduced the expression of various SASP components, thereby ameliorating the negative influence on nearby cells. Thus, the investigated plant extract represents a promising possibility to block age-related loss of tissue functionality.

This randomized, placebo-controlled, crossover, double-blind trial aimed to evaluate the efficacy and safety of Tacrosolv, a novel 0.005% tacrolimus eye-drop solution, in adults with grass pollen-induced allergic conjunctivitis. A total of 64 adult participants were randomized to receive 2.5 µg or 5 µg tacrolimus/eye/day or placebo treatment for 8 days, with grass pollen exposure on day 1 and day 8. After a 2-week washout period, placebo participants crossed over to Tacrosolv treatment and vice versa, with repeated treatment and exposure. During exposure, participants recorded ocular, nasal, and respiratory allergy symptoms every 15 minutes. The primary endpoint was the mean total ocular symptom score (TOSS) on day 8. Objective ocular safety parameters were assessed before, during, and after exposure. Adverse events were recorded throughout the study. On day 8, high-dose Tacrosolv reduced the TOSS compared to placebo towards the end of exposure ( <0.05 at time points 3 hours, 45 minutes and 4 hours). A 26% reduction in baseline adjusted TOSS from day 1 to day 8 was observed in participants treated with high-dose Tacrosolv, whereas placebo-treated participants showed no difference in TOSS between day 1 and day 8. Nasal symptoms were reduced on both day 1 and day 8 in participants treated with high-dose Tacrosolv ( <0.05). No safety concerns were raised. All adverse events were resolved within the study period. High-dose Tacrosolv is safe and effective for alleviating symptoms of allergic rhinoconjunctivitis. NCT04532710; EudraCT No. 2019-002847-62.

This study aimed to develop a hyperosmolar, barrier-forming nasal spray based on carrageenan and sorbitol, and to demonstrate its decongestant effect in the context of allergic rhinitis (AR). The efficacy of the nasal spray components was tested in vitro by barrier function, virus replication inhibition, and water absorption assays. The decongestant effectiveness was assessed in a randomized, controlled, crossover environmental chamber trial, where participants with a history of seasonal grass pollen AR were exposed to grass pollen allergens under controlled conditions. Forty-one adults were randomized to receive either carrageenan- and sorbitol-containing nasal spray (CS) or saline solution (SS). After 1 week, participants repeated the exposure with the treatment they had not received before. The primary efficacy endpoint was the mean change in nasal congestion symptom score (NCSS). Secondary efficacy endpoints were nasal airflow, nasal secretion, total nasal symptom score (TNSS), total ocular symptom score (TOSS) and total respiratory symptom score (TRSS). Preclinical assays demonstrated barrier-building, virus-blocking, and water-withdrawing properties of the CS components. In the clinical study, there was no significant difference in mean NCSS change from pre- to post-treatment between CS and SS. However, nasal airflow increased over time after treatment with CS, while it declined after SS, leading to a growing difference in airflow between CS and SS (p = 0.04 at 6:00 h). Mean nasal secretion over 2-6 h was reduced by ~25% after CS (p = 0.003) compared to pre-treatment, while it was reduced by only ~16% after SS (p = 0.137). No significant differences in TNSS, TOSS and TRSS were observed between CS and SS. CS improves nasal airflow and reduces nasal secretion in adults with AR. We propose CS as a safe and effective adjuvant to baseline pharmacological treatments. NCT04532762.

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

Members of the MOAG/SERF protein family have been attributed a neuropathologic significance because of their ability to enhance the proteotoxic polymerization of amyloidogenic proteins such as alpha-Synuclein (aSyn). However, the cellular function remains unknown. Here, we identify SERF1a as an RNA-organizing protein i) with no structural homology to canonical RNA-binding proteins, ii) with an RNA-chaperoning activity which favours the incorporation of RNA into nucleoli and liquid-like artificial RNA-organelles, and iii) with a high degree of conformational disorder in the RNA-bound state. We demonstrate that this type of structural fuzziness determines an undifferentiated interaction of SERF1a with aSyn and RNA. Both molecules bind to one identical, positively charged site of SERF1a by an analogous electrostatic binding mode, with similar binding affinities, and without any observable disorder-to-order transition. The absence of primary or secondary structure discriminants results in SERF1a being unable to distinguish between nucleic acid and amyloidogenic protein, leading the pro-amyloid aSyn:SERF1a interaction to prevail under conditions of cellular stress. We suggest that structural fuzziness of SERF1a accounts for an adverse gain-of-interaction which favours toxic binding to aSyn at the expense of non-toxic RNA binding, therefore promoting a functionally distorted and pathogenic process. Our results provide a direct link between structural disorder, amyloid aggregation and the malfunctioning of RNA-associated cellular processes, three hallmarks of neurodegenerative diseases.