Abstract: “Exercise enhances synaptic plasticity and alleviates depression symptoms, but the mechanism through which exercise improves high-fat diet-induced depression remains unclear. In this study, 6-week-old male C57BL/6J mice were administered a high-fat diet (HFD, 60% kcal from fat) to a HFD model for 8 weeks. The RUN group also received 1 h of daily treadmill exercise in combination with the HFD. Depressive-like behaviors were evaluated by behavioral assessments for all groups. The key mediator of the effect of exercise on high-fat diet-induced depressive-like behaviors was detected by RNA-seq. The morphology and function of the neurons were evaluated via Nissl staining, Golgi staining, electron microscopy and electrophysiological experiments. The results showed that exercise attenuated high-fat diet-induced depressive-like behavior and reversed hippocampal gene expression changes. RNA-seq revealed Wnt5a, which was a key mediator of the effect of exercise on high-fat diet-induced depressive-like behaviors. Further work revealed that exercise significantly activated neuronal autophagy in the hippocampal CA1 region via the Wnt5a/CamkII signaling pathway, which enhanced synaptic plasticity to alleviate HFD-induced depressive-like behavior. However, the Wnt5a inhibitor Box5 suppressed the ameliorative effects of exercise. Therefore, this work highlights the critical role of Wnt5a, which is necessary for exercise to improve high-fat diet-induced depression.”

Wu, J., Xu, H., Wang, S. et al. Regular exercise ameliorates high-fat diet-induced depressive-like behaviors by activating hippocampal neuronal autophagy and enhancing synaptic plasticity. Cell Death Dis 15, 737 (2024). https://doi.org/10.1038/s41419-024-07132-4

https://www.nature.com/articles/s41419-024-07132-4

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Abstract: Caloric restriction extends healthy lifespan in multiple species. Intermittent fasting, an alternative form of dietary restriction, is potentially more sustainable in humans, but its effectiveness remains largely unexplored. Identifying the most efficacious forms of dietary restriction is key for developing interventions to improve human health and longevity. Here we performed an extensive assessment of graded levels of caloric restriction (20% and 40%) and intermittent fasting (1 and 2 days fasting per week) on the health and survival of 960 genetically diverse female mice. We show that caloric restriction and intermittent fasting both resulted in lifespan extension in proportion to the degree of restriction. Lifespan was heritable and genetics had a larger influence on lifespan than dietary restriction. The strongest trait associations with lifespan included retention of body weight through periods of handling—an indicator of stress resilience, high lymphocyte proportion, low red blood cell distribution width and high adiposity in late life. Health effects differed between interventions and exhibited inconsistent relationships with lifespan extension. 40% caloric restriction had the strongest lifespan extension effect but led to a loss of lean mass and changes in the immune repertoire that could confer susceptibility to infections. Intermittent fasting did not extend the lifespan of mice with high pre-intervention body weight, and two-day intermittent fasting was associated with disruption of erythroid cell populations. Metabolic responses to dietary restriction, including reduced adiposity and lower fasting glucose, were not associated with increased lifespan, suggesting that dietary restriction does more than just counteract the negative effects of obesity. Our findings indicate that improving health and extending lifespan are not synonymous and raise questions about which end points are the most relevant for evaluating aging interventions in preclinical models and clinical trials.

Di Francesco, A., Deighan, A.G., Litichevskiy, L. et al. Dietary restriction impacts health and lifespan of genetically diverse mice. Nature (2024). https://doi.org/10.1038/s41586-024-08026-3

https://www.nature.com/articles/s41586-024-08026-3

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Climbing stairs is associated with a longer life, according to research presented today at ESC Preventive Cardiology 2024, a scientific congress of the European Society of Cardiology (ESC).1

“If you have the choice of taking the stairs or the lift, go for the stairs as it will help your heart,” said study author Dr. Sophie Paddock of the University of East Anglia and Norfolk and Norwich University Hospital Foundation Trust, Norwich, UK. “Even brief bursts of physical activity have beneficial health impacts, and short bouts of stair climbing should be an achievable target to integrate into daily routines.”

Cardiovascular disease is largely preventable2 through actions like exercise.

However, more than one in four adults worldwide do not meet recommended levels of physical activity.3 Stair climbing is a practical and easily accessible form of physical activity which is often overlooked.

This study investigated whether climbing stairs, as a form of physical activity, could play a role in reducing the risks of cardiovascular disease and premature death.

The authors collected the best available evidence on the topic and conducted a meta-analysis.

Studies were included regardless of the number of flights of stairs and the speed of climbing.

There were nine studies with 480,479 participants in the final analysis.

The study population included both healthy participants and those with a previous history of heart attack or peripheral arterial disease.

Ages ranged from 35 to 84 years old and 53% of participants were women.

Compared with not climbing stairs, stair climbing was associated with a 24% reduced risk of dying from any cause4 and a 39% lower likelihood of dying from cardiovascular disease.5 Stair climbing was also linked with a reduced risk of cardiovascular disease including heart attack, heart failure and stroke.

Dr. Paddock said: “Based on these results, we would encourage people to incorporate stair climbing into their day-to-day lives. Our study suggested that the more stairs climbed, the greater the benefits — but this needs to be confirmed. So, whether at work, home, or elsewhere, take the stairs.”

1The abstract ‘Evaluating the cardiovascular benefits of stair climbing: a systematic review and meta-analysis’ will be presented during the session ‘Optimal exercise modalities for primary and secondary prevention’ which takes place on 26 April 2024 at Moderated ePosters 1.

2Timmis A, Vardas P, Townsend N, et al. European Society of Cardiology: cardiovascular disease statistics 2021.

Eur Heart J. 2022;43:716-799.

3World Health Organization: Physical activity.

4Relative risk 0.76, 95% confidence interval 0.62-0.94, p=0.01.

5Relative risk 0.61, 95% confidence interval 0.48-0.79, p=0.0002

https://www.sciencedaily.com/releases/2024/04/240426110051.htm

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Abstract:

Dopamine’s role as the principal neurotransmitter in motor functions has long been accepted. We broaden this conventional perspective by demonstrating the involvement of non-dopaminergic mechanisms. In mouse models of Parkinson’s disease, we observed that L-DOPA elicited a substantial motor response even when its conversion to dopamine was blocked by inhibiting the enzyme aromatic amino acid decarboxylase (AADC). Remarkably, the motor activity response to L-DOPA in the presence of an AADC inhibitor (NSD1015) showed a delayed onset, yet greater intensity and longer duration, peaking at 7 h, compared to when L-DOPA was administered alone. This suggests an alternative pathway or mechanism, independent of dopamine signalling, mediating the motor functions. We sought to determine the metabolites associated with the pronounced hyperactivity observed, using comprehensive metabolomics analysis.

Our results revealed that the peak in motor activity induced by NSD1015/L-DOPA in Parkinson’s disease mice is associated with a surge (20-fold) in brain levels of the tripeptide ophthalmic acid (also known as ophthalmate in its anionic form). Interestingly, we found that administering ophthalmate directly to the brain rescued motor deficits in Parkinson’s disease mice in a dose-dependent manner. We investigated the molecular mechanisms underlying ophthalmate’s action and discovered, through radioligand binding and cAMP-luminescence assays, that ophthalmate binds to and activates the calcium-sensing receptor (CaSR).

Additionally, our findings demonstrated that a CaSR antagonist inhibits the motor-enhancing effects of ophthalmate, further solidifying the evidence that ophthalmate modulates motor functions through the activation of the CaSR. The discovery of ophthalmate as a novel regulator of motor function presents significant potential to transform our understanding of brain mechanisms of movement control and the therapeutic management of related disorders.

Sammy Alhassen, Derk Hogenkamp, Hung Anh Nguyen, Saeed Al Masri, Geoffrey W Abbott, Olivier Civelli, Amal Alachkar, Ophthalmate is a new regulator of motor functions via CaSR: implications for movement disorders, Brain, Volume 147, Issue 10, October 2024, Pages 3379–3394, https://doi.org/10.1093/brain/awae097

https://academic.oup.com/brain/article/147/10/3379/7636309

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Abstract: 

Background: Smoking is the leading behavioural risk factor for mortality globally, accounting for more than 175 million deaths and nearly 4·30 billion years of life lost (YLLs) from 1990 to 2021. The pace of decline in smoking prevalence has slowed in recent years for many countries, and although strategies have recently been proposed to achieve tobacco-free generations, none have been implemented to date. Assessing what could happen if current trends in smoking prevalence persist, and what could happen if additional smoking prevalence reductions occur, is important for communicating the effect of potential smoking policies.

Methods: In this analysis, we use the Institute for Health Metrics and Evaluation’s Future Health Scenarios platform to forecast the effects of three smoking prevalence scenarios on all-cause and cause-specific YLLs and life expectancy at birth until 2050. YLLs were computed for each scenario using the Global Burden of Disease Study 2021 reference life table and forecasts of cause-specific mortality under each scenario. The reference scenario forecasts what could occur if past smoking prevalence and other risk factor trends continue, the Tobacco Smoking Elimination as of 2023 (Elimination-2023) scenario quantifies the maximum potential future health benefits from assuming zero percent smoking prevalence from 2023 onwards, whereas the Tobacco Smoking Elimination by 2050 (Elimination-2050) scenario provides estimates for countries considering policies to steadily reduce smoking prevalence to 5%. Together, these scenarios underscore the magnitude of health benefits that could be reached by 2050 if countries take decisive action to eliminate smoking. The 95% uncertainty interval (UI) of estimates is based on the 2·5th and 97·5th percentile of draws that were carried through the multistage computational framework.

Findings: Global age-standardised smoking prevalence was estimated to be 28·5% (95% UI 27·9-29·1) among males and 5·96% (5·76-6·21) among females in 2022. In the reference scenario, smoking prevalence declined by 25·9% (25·2-26·6) among males, and 30·0% (26·1-32·1) among females from 2022 to 2050. Under this scenario, we forecast a cumulative 29·3 billion (95% UI 26·8-32·4) overall YLLs among males and 22·2 billion (20·1-24·6) YLLs among females over this period. Life expectancy at birth under this scenario would increase from 73·6 years (95% UI 72·8-74·4) in 2022 to 78·3 years (75·9-80·3) in 2050. Under our Elimination-2023 scenario, we forecast 2·04 billion (95% UI 1·90-2·21) fewer cumulative YLLs by 2050 compared with the reference scenario, and life expectancy at birth would increase to 77·6 years (95% UI 75·1-79·6) among males and 81·0 years (78·5-83·1) among females. Under our Elimination-2050 scenario, we forecast 735 million (675-808) and 141 million (131-154) cumulative YLLs would be avoided among males and females, respectively. Life expectancy in 2050 would increase to 77·1 years (95% UI 74·6-79·0) among males and 80·8 years (78·3-82·9) among females.

Interpretation: Existing tobacco policies must be maintained if smoking prevalence is to continue to decline as forecast by the reference scenario. In addition, substantial smoking-attributable burden can be avoided by accelerating the pace of smoking elimination. Implementation of new tobacco control policies are crucial in avoiding additional smoking-attributable burden in the coming decades and to ensure that the gains won over the past three decades are not lost.

GBD 2021 Tobacco Forecasting Collaborators. Forecasting the effects of smoking prevalence scenarios on years of life lost and life expectancy from 2022 to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Public Health. 2024 Oct;9(10):e729-e744. doi: 10.1016/S2468-2667(24)00166-X. PMID: 39366729.

https://pubmed.ncbi.nlm.nih.gov/39366729/

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Highlights

  • Athletes exhibited lower baseline BDNF levels compared to sedentary individuals.
  • BDNF serum levels increased after a single session of acute aerobic exercise.
  • The response to serum levels of BDNF depends on different levels of physical activity.
  • A single session of acute aerobic exercise is insufficient to enhance executive function.

Beatriz Muñoz Ospina, Natalia Cadavid-Ruiz, The effect of aerobic exercise on serum brain-derived neurotrophic factor (BDNF) and executive function in college students, Mental Health and Physical Activity, Volume 26,2024,100578, https://doi.org/10.1016/j.mhpa.2024.100578.

https://www.sciencedirect.com/science/article/pii/S1755296624000036

See also:

Tang SW, Chu E, Hui T, Helmeste D, Law C. Influence of exercise on serum brain-derived neurotrophic factor concentrations in healthy human subjects. Neurosci Lett. 2008 Jan 24;431(1):62-5. doi: 10.1016/j.neulet.2007.11.019. Epub 2007 Nov 17. PMID: 18068900.

https://pubmed.ncbi.nlm.nih.gov/18068900/

 

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Abstract: Multiple sclerosis (MS) is an inflammatory neurological disease of the central nervous system with a subclinical phase preceding frank neuroinflammation. CD8+ T cells are abundant within MS lesions, but their potential role in disease pathology remains unclear. Using high-throughput single-cell RNA sequencing and single-cell T cell receptor analysis, we compared CD8+ T cell clones from the blood and cerebrospinal fluid (CSF) of monozygotic twin pairs in which the cotwin had either no or subclinical neuroinflammation (SCNI). We identified peripheral MS-associated immunological and metabolic alterations indicative of an enhanced migratory, proinflammatory, and activated CD8+ T cell phenotype, which was also evident in cotwins with SCNI and in an independent validation cohort of people with MS. Together, our in-depth single-cell analysis indicates a disease-driving proinflammatory role of infiltrating CD8+ T cells and identifies potential immunological and metabolic therapeutic targets in both prodromal and definitive stages of the disease.

Kavaka V., et al., Twin study identifies early immunological and metabolic dysregulation of CD8+ T cells in multiple sclerosis.  Science Immunology 9(99), 27 Sept.2024:    DOI: 10.1126/sciimmunol.adj8094

https://www.science.org/doi/10.1126/sciimmunol.adj8094

 

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Abstract:

Progressive multiple sclerosis poses a considerable challenge in the evaluation of disease progression and treatment response owing to its multifaceted pathophysiology. Traditional clinical measures such as the Expanded Disability Status Scale are limited in capturing the full scope of disease and treatment effects. Advanced imaging techniques, including MRI and PET scans, have emerged as valuable tools for the assessment of neurodegenerative processes, including the respective role of adaptive and innate immunity, detailed insights into brain and spinal cord atrophy, lesion dynamics and grey matter damage. The potential of cerebrospinal fluid and blood biomarkers is increasingly recognized, with neurofilament light chain levels being a notable indicator of neuro-axonal damage. Moreover, patient-reported outcomes are crucial for reflecting the subjective experience of disease progression and treatment efficacy, covering aspects such as fatigue, cognitive function and overall quality of life. The future incorporation of digital technologies and wearable devices in research and clinical practice promises to enhance our understanding of functional impairments and disease progression. This Review offers a comprehensive examination of these diverse evaluation tools, highlighting their combined use in accurately assessing disease progression and treatment efficacy in progressive multiple sclerosis, thereby guiding more effective therapeutic strategies.

Key points

  • Effective treatment of progressive multiple sclerosis (MS) remains an urgent medical need.
  • The recent approvals of treatments for progressive forms of MS highlight the importance of better disease monitoring measures in clinical trials and practice.
  • Traditional MRI biomarkers do not adequately track progressive MS. Advances in MRI, such as brain atrophy and lesion volume analysis, show promise in assessing disease progression and response to treatment.
  • Remyelination is key in MS neuroprotection. MRI techniques such as magnetization transfer and myelin water fraction imaging, alongside PET scans, provide deeper insights into myelin repair and inflammation.
  • Changes in optical coherence tomography, a non-invasive imaging modality that measures retinal layer thickness, reflect brain atrophy and MS progression, offering a valuable window into neurodegeneration and treatment efficacy.
  • Body fluid biomarkers, such as neurofilament light in blood, and immune activation and neuronal damage markers in cerebrospinal fluid are emerging as important tools for assessing disease activity and treatment response in progressive MS.
  • Patient-reported outcomes capture the unique experience of individuals with MS, which is of particular importance in progressive forms of the disease. These assessments can help evaluate hidden symptoms such as fatigue and cognitive impairment and are becoming vital in clinical trials and routine practice.

Comi, G., Dalla Costa, G., Stankoff, B. et al. Assessing disease progression and treatment response in progressive multiple sclerosis. Nat Rev Neurol 20, 573–586 (2024). https://doi.org/10.1038/s41582-024-01006-1

https://www.nature.com/articles/s41582-024-01006-1

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Abstract:  Exercise training represents a health behavior for the treatment and management of the multi-faceted manifestations of multiple sclerosis (MS). This paper provides a comprehensive overview of evidence from randomized controlled trials (RCTs) regarding benefits, safety, participation, and guidelines for exercise training in MS, based on systematic reviews and meta-analyses. The paper then provides our opinions based on extensive experience regarding challenges for improving and expanding future RCTs that will advance our understanding of exercise training in MS. The comprehensive review of evidence from RCTs indicates that exercise training yields substantial improvements in aerobic and muscle fitness, mobility, fatigue and depression, quality of life, and participation outcomes. There is a non-significant increase in the risk of adverse events or serious adverse events with exercise training compared with control conditions or healthy populations. Rates of adherence and compliance with exercise training (i.e., participation) approximate 80% and 70%, respectively. The current prescriptive guidelines suggest 2-3 days per week of aerobic and resistance exercise training as the minimal dose for safely benefiting from exercise training in MS. We propose 10 important topics as avenues for expanding the body of research and improving its scope for evidence-based practice in MS. Overall, the research on exercise training in MS is strong, but it can get stronger. The expansion and advancement of evidence are critical for moving exercise training into the clinical armamentarium of MS disease treatment and management.

Motl RW, Pilutti LA. Advancements and Challenges in Exercise Training for Multiple Sclerosis: Comprehensive Review and Future Directions for Randomized Controlled Trials. Neurol Ther. 2024 Sep 13. doi: 10.1007/s40120-024-00656-z. Epub ahead of print. PMID: 39271645.

https://pubmed.ncbi.nlm.nih.gov/39271645/

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Abstract: Kawasaki disease is an acute, self-limiting, systemic vasculitis of small and medium-sized arteries. It predominantly occurs in children under 4 years of age, though rarely older children can also be affected. This disease is the leading cause of acquired heart disease in children, with coronary aneurysms being a hallmark finding. The risk of coronary complications necessitates regular monitoring and possible preventative treatment with thromboprophylaxis. Here we discuss a rare case of a 10-year-old boy who exhibited typical symptoms of Kawasaki disease and was found to have multiple coronary artery aneurysms through diagnostic imaging.

Wagle G, Khatiwada A, Bastakoti S, K C S. Late onset Kawasaki disease with multiple coronary arterial aneurysms: A case report. Radiol Case Rep. 2024 Aug 10;19(11):4762-4765. doi: 10.1016/j.radcr.2024.07.066. PMID: 39228940; PMCID: PMC11366877.

https://pubmed.ncbi.nlm.nih.gov/39228940/

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