Pharmacological inhibition of USP14 delays proteostasis-associated aging in a proteasome-dependent but foxo-independent manner.

Aging is often accompanied by a decline in proteostasis, manifested as an increased propensity for misfolded protein aggregates, which are prevented by protein quality control systems, such as the ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. Although the role of the UPS and autophagy in slowing age-induced proteostasis decline has been elucidated, limited information is available on how these pathways can be activated in a collaborative manner to delay proteostasis-associated aging. Here, we show that activation of the UPS via the pharmacological inhibition of USP14 (ubiquitin specific peptidase 14) using IU1 improves proteostasis and autophagy decline caused by aging or proteostatic stress in Drosophila and human cells. Treatment with IU1 not only alleviated the aggregation of polyubiquitinated proteins in aging Drosophila flight muscles but also extended the fly lifespan with enhanced locomotive activity via simultaneous activation of the UPS and autophagy. Interestingly, the effect of this drug disappeared when proteasomal activity was inhibited, but was evident upon proteostasis disruption by foxo mutation. Overall, our findings shed light on potential strategies to efficiently ameliorate age-associated pathologies associated with perturbed proteostasis.

Minocycline treatment improves proteostasis during Drosophila aging via autophagy mediated by FOXO and Hsp70.

Minocycline is a semi-synthetic tetracycline derivative antibiotic that has been examined for its non-antibiotic properties, such as anti-inflammatory, tumor-suppressive, and neuroprotective effects. In this study, we found that feeding minocycline to Drosophila improves proteostasis during organismal aging. Poly-ubiquitinated protein aggregates increase in the flight muscles as flies age, which are reduced in response to minocycline feeding. Minocycline feeding increases the expression of several autophagy genes and the activity of the autophagy/lysosomal pathway in Drosophila muscles. Interestingly, mutant flies lacking either FOXO or Hsp70 showed increased levels of poly-ubiquitinated protein aggregates with reduced autophagy/lysosomal activity, which was not reversed by minocycline feeding. Our findings suggest that minocycline may improve proteostasis in aging tissues via FOXO-Hsp70 axis, which highlights the multifaceted effects of minocycline as a therapeutic agent in age-associated features.

Paraburkholderia lacunae sp. nov., isolated from soil near an artificial pond.

A Gram-stain-negative, strictly aerobic bacterial strain, designated strain S27T, was isolated from soil near an artificial pond in South Korea. Cells were non-motile short rods showing oxidase- and catalase-positive activities. Growth of strain S27T was observed at 20-40°C (optimum, 30°C), pH 5.0-7.0 (optimum, pH 6.0), and 0-0.5% (w/v) NaCl (optimum, 0%). Ubiquinone-8 was detected as the sole respiratory quinone and the major fatty acids were C16:0, cyclo-C17:0, and cyclo-C19:0ω8c. The G + C content of the genomic DNA was 62.4 mol%. Phosphatidylglycerol, phosphatidylethanolamine, and an unidentified aminophospholipid were detected as the major polar lipids. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain S27T formed a clearly distinct phyletic lineage from closely related Paraburkholderia species within the genus Paraburkholderia. Strain S27T was most closely related to Paraburkholderia rhynchosiae WSM3937T, Paraburkholderia ginsengiterrae DCY85T, Paraburkholderia fungorum NBRC 102489T, and Paraburkholderia graminis C4D1MT with 98.8%, 98.4%, 98.4%, and 97.7% 16S rRNA gene sequence similarities, respectively. The DNA-DNA relatedness level between strain S27T and the type strain of P. rhynchosiae was 36.8 ± 2.6%. On the basis of phenotypic, chemotaxonomic and molecular properties, strain S27T represents a novel species of the genus Paraburkholderia, for which the name Paraburkholderia lacunae sp. nov. is proposed. The type strain is S27T (KACC 19714 T = JCM 32721T).

Steroid signaling mediates nutritional regulation of juvenile body growth via IGF-binding protein in Drosophila.

Nutritional condition during the juvenile growth period considerably affects final adult size. The insulin/insulin-like growth factor signaling (IIS)/target of rapamycin (TOR) nutrient-sensing pathway is known to regulate growth and metabolism in response to nutritional conditions. However, there is limited information on how endocrine pathways communicate nutritional information to different metabolic organs to regulate organismal growth. Here, we show that Imaginal morphogenesis protein-Late 2 (Imp-L2), a Drosophila homolog of insulin-like growth factor-binding protein 7 (IGFBP7), plays a key role in the nutritional control of organismal growth. Nutritional restriction during the larval growth period causes undersized adults, which is largely diminished by Imp-L2 mutation. We delineate a pathway in which nutritional restriction increases levels of the steroid hormone ecdysone, which, in turn, triggers ecdysone signaling-dependent Imp-L2 production from the fat body, a fly adipose organ, thereby attenuating peripheral IIS and body growth. Surprisingly, this endocrine pathway operates independent of the fat-body-TOR internal nutrient sensor, long believed to be the control center for nutrition-dependent growth. Our study reveals a previously unrecognized endocrine circuit mediating nutrition-dependent juvenile growth, which could also potentially be related to the insulin resistance frequently observed in puberty.

Minocycline treatment increases resistance to oxidative stress and extends lifespan in Drosophila via FOXO.

Minocycline is a semi-synthetic tetracycline derivative antibiotic that has received increasing attention for its non-antibiotic properties, mainly anti-inflammatory, tumor-suppressive, and neuroprotective effects. Drosophila is a widely used genetically tractable model organism for studying organismal aging by virtue of its short lifespan and ease of cultivation. In this study, we examined the effects of minocycline on Drosophila lifespan and its associated traits. Minocycline-supplemented food significantly extended lifespan in both Canton S and w1118 Drosophila strains. The drug-induced lifespan extension was not associated with reduced dietary intake or reduced female fecundity, but rather with increased resistance to an oxidative stressor (hydrogen peroxide). Notably, minocycline's effects on lifespan and resistance to oxidative stress were largely abrogated in Forkhead box O (FOXO) null mutant, and the drug treatment increased the activity of FOXO. These results may further our understanding of minocycline's beneficial effects against several age-associated deteriorations observed in animal models.