Lifespan Control by Redox-Dependent Recruitment of Chaperones to Misfolded Proteins.

Caloric restriction (CR) extends the lifespan of flies, worms, and yeast by counteracting age-related oxidation of H2O2-scavenging peroxiredoxins (Prxs). Here, we show that increased dosage of the major cytosolic Prx in yeast, Tsa1, extends lifespan in an Hsp70 chaperone-dependent and CR-independent manner without increasing H2O2 scavenging or genome stability. We found that Tsa1 and Hsp70 physically interact and that hyperoxidation of Tsa1 by H2O2 is required for the recruitment of the Hsp70 chaperones and the Hsp104 disaggregase to misfolded and aggregated proteins during aging, but not heat stress. Tsa1 counteracted the accumulation of ubiquitinated aggregates during aging and the reduction of hyperoxidized Tsa1 by sulfiredoxin facilitated clearance of H2O2-generated aggregates. The data reveal a conceptually new role for H2O2 signaling in proteostasis and lifespan control and shed new light on the selective benefits endowed to eukaryotic peroxiredoxins by their reversible hyperoxidation.

Living a longer life: unique lessons from the naked mole-rat blood system.

Analysis of functional deterioration of the blood system during ageing has been largely confined to the mouse and human system. In this issue, Emmrich et al (2022) report the first comprehensive characterisation of the haematopoietic system of the naked mole-rat (NMR), an exceptionally long-lived rodent, highlighting its unique features and uncovering potential strategies to sustain haematopoiesis during an extended lifetime.

Differential role of cytosolic Hsp70s in longevity assurance and protein quality control.

70 kDa heat shock proteins (Hsp70) are essential chaperones of the protein quality control network; vital for cellular fitness and longevity. The four cytosolic Hsp70's in yeast, Ssa1-4, are thought to be functionally redundant but the absence of Ssa1 and Ssa2 causes a severe reduction in cellular reproduction and accelerates replicative aging. In our efforts to identify which Hsp70 activities are most important for longevity assurance, we systematically investigated the capacity of Ssa4 to carry out the different activities performed by Ssa1/2 by overproducing Ssa4 in cells lacking these Hsp70 chaperones. We found that Ssa4, when overproduced in cells lacking Ssa1/2, rescued growth, mitigated aggregate formation, restored spatial deposition of aggregates into protein inclusions, and promoted protein degradation. In contrast, Ssa4 overproduction in the Hsp70 deficient cells failed to restore the recruitment of the disaggregase Hsp104 to misfolded/aggregated proteins, to fully restore clearance of protein aggregates, and to bring back the formation of the nucleolus-associated aggregation compartment. Exchanging the nucleotide-binding domain of Ssa4 with that of Ssa1 suppressed this 'defect' of Ssa4. Interestingly, Ssa4 overproduction extended the short lifespan of ssa1Δ ssa2Δ mutant cells to a lifespan comparable to, or even longer than, wild type cells, demonstrating that Hsp104-dependent aggregate clearance is not a prerequisite for longevity assurance in yeast.

Empowered and engaged: Group exercise for adolescent depression - perspectives from adolescents, parents and healthcare professionals.

Objectives: Depression is increasing and is a leading cause of disease burden among adolescents. Available evidence-based treatments with medication or psychotherapy have modest effects. Aerobic exercise is a hopeful alternative as an augmenter or a stand-alone treatment. Qualitative studies have shown that participants in group exercise for adolescent depression experienced improved mood and a sense of achievement, commitment and empowerment. This study aimed to explore not only adolescents' but also parents' and healthcare professionals' experiences of a group exercise intervention for adolescents with depression. Methods: Nine adolescents who had participated in a group aerobic exercise intervention for 12 weeks, eight parents and two healthcare professionals were interviewed. We used a latent qualitative content analysis with an inductive approach that resulted in nine sub-categories, three categories and an overarching theme. Results: The experiences of a group exercise intervention for adolescents with depression were expressed in the overarching theme 'Group exercise for adolescent depression promotes empowerment and engagement in everyday life', based on three categories: exercise alleviates depressive symptoms, exercise contributes to balance in life and exercise promotes self-esteem. However, there was variation in our results, in that not all participants experienced improvements from exercising. Adolescents described more varied experiences, while parents and healthcare professionals mainly expressed positive views. Conclusions: Our findings suggest that group exercise for adolescent depression promotes empowerment and engagement in everyday life, according to adolescents, and more clearly so according to parents and healthcare professionals.

Single-blinded, randomised, parallel-group, controlled trial comparing the efficacy and cost-effectiveness of therapist- and self-guided internet-delivered behavioural activation versus treatment as usual for adolescents with mild to moderate depression: study protocol.

INTRODUCTION: The number of adolescents seeking professional help for depression is increasing and, despite advances in treatment, large unmet treatment needs remain. In the current protocol, we describe the design and methodology of a randomised controlled trial (RCT) to evaluate the clinical efficacy of two forms of internet-delivered behavioural activation (I-BA), with and without therapist support, in reducing depressive symptoms, compared with treatment as usual (TAU). Secondary objectives include examining the 12-month maintenance of the treatment effects and conducting a health economic evaluation of the interventions. METHODS AND ANALYSIS: In this single-blinded RCT, we aim to include 215 participants aged 13-17 years with mild to moderate depression who will be randomised (1:1:1 ratio) to 10 weeks of either therapist-guided or self-guided I-BA, or TAU provided by regular mental health clinics. Data will be collected at baseline, weekly for the initial 10 weeks, post-treatment and at 3 and 12-month follow-ups. The primary endpoint is the 3-month follow-up. The primary outcome is blinded clinician-rated severity of depressive symptoms, measured by the Children's Depression Rating Scale-Revised. Treatment response is defined as a score of 'Much improved' or 'Very much improved' on the Clinical Global Impression-Improvement Scale, administered at the primary endpoint. Outcome assessors will be blinded to treatment conditions at all assessment points. A health economic evaluation of I-BA will be performed, both in the short term (primary endpoint) and the long term (12-month follow-up). ETHICS AND DISSEMINATION: Ethical approval was obtained from the Swedish Ethical Review Authority in June 2021. The final participant was enrolled on 3 May 2024 and expected to reach the primary endpoint by November 2024. The results of this study will be disseminated through publication in peer-reviewed journals, presented at conferences and communicated to healthcare providers and the public. TRIAL REGISTRATION NUMBER: NCT04977856.

Improving mental health among intensive care unit staff with communication skills training.

Purpose: Intensive Care Unit (ICU) staff report that a large part of the work-related distress they experience is related to communication situations with colleagues, patients, and relatives. Based on these findings, the aim of the present study was to preliminary evaluate the effects of a novel Communication Skills Training (CST) program on mental health among ICU staff. Methods: The CST program was delivered to the entire work force of an ICU at a Swedish hospital and was evaluated as an uncontrolled clinical trial with three repeated measures. 100 participants were eligible and included in the analyses. The theoretical framework for the program was learning theory and cognitive behavioral therapy. The program was delivered by two psychologists and included one full-day lecture and three subsequent two-hour supervision sessions. Changes in mental health was evaluated with self-report questionnaires measuring perceived stress, general mental health, work engagement, and psychological flexibility. Results: Analyses of three repeated measures showed significant improvements with 1.3 points lower perceived stress and 2.0 points lower general mental health after the intervention. No differences were seen in measures of work engagement or psychological flexibility. Conclusion: Findings of the study supports the utility of the CST program as an intervention to target perceived stress and general mental health within intensive care. These findings should be further validated in trials with improved design.

How and why do toxic conformers of aberrant proteins accumulate during ageing?

Ageing can be defined as a gradual decline in cellular and physical functions accompanied by an increased sensitivity to the environment and risk of death. The increased risk of mortality is causally connected to a gradual, intracellular accumulation of so-called ageing factors, of which damaged and aggregated proteins are believed to be one. Such aggregated proteins also contribute to several age-related neurodegenerative disorders e.g. Alzheimer's, Parkinson's, and Huntington's diseases, highlighting the importance of protein quality control (PQC) in ageing and its associated diseases. PQC consists of two interrelated systems: the temporal control system aimed at refolding, repairing, and/or removing aberrant proteins and their aggregates and the spatial control system aimed at harnessing the potential toxicity of aberrant proteins by sequestering them at specific cellular locations. The accumulation of toxic conformers of aberrant proteins during ageing is often declared to be a consequence of an incapacitated temporal PQC system-i.e. a gradual decline in the activity of chaperones and proteases. Here, we review the current knowledge on PQC in relation to ageing and highlight that the breakdown of both temporal and spatial PQC may contribute to ageing and thus comprise potential targets for therapeutic interventions of the ageing process.