Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia:Recent Progress on the Mechanisms and Interventional Strategies

Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a "Money Follows Cooperation agreement" between the 2 nations. The inaugural Norway-UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.</p

A randomized controlled trial on the effectiveness of strength training on clinical and muscle cellular outcomes in patients with prostate cancer during androgen deprivation therapy: rationale and design

Background Studies indicate that strength training has beneficial effects on clinical health outcomes in prostate cancer patients during androgen deprivation therapy. However, randomized controlled trials are needed to scientifically determine the effectiveness of strength training on the muscle cell level. Furthermore, close examination of the feasibility of a high-load strength training program is warranted. The Physical Exercise and Prostate Cancer (PEPC) trial is designed to determine the effectiveness of strength training on clinical and muscle cellular outcomes in non-metastatic prostate cancer patients after high-dose radiotherapy and during ongoing androgen deprivation therapy. Methods/design Patients receiving androgen deprivation therapy for 9-36 months combined with external high-dose radiotherapy for locally advanced prostate cancer are randomized to an exercise intervention group that receives a 16 week high-load strength training program or a control group that is encouraged to maintain their habitual activity level. In both arms, androgen deprivation therapy is continued until the end of the intervention period. Clinical outcomes are body composition (lean body mass, bone mineral density and fat mass) measured by Dual-energy X-ray Absorptiometry, serological outcomes, physical functioning (muscle strength and cardio-respiratory fitness) assessed with physical tests and psycho-social functioning (mental health, fatigue and health-related quality of life) assessed by questionnaires. Muscle cellular outcomes are a) muscle fiber size b) regulators of muscle fiber size (number of myonuclei per muscle fiber, number of satellite cells per muscle fiber, number of satellite cells and myonuclei positive for androgen receptors and proteins involved in muscle protein degradation and muscle hypertrophy) and c) regulators of muscle fiber function such as proteins involved in cellular stress and mitochondrial function. Muscle cellular outcomes are measured on muscle cross sections and muscle homogenate from muscle biopsies obtained from muscle vastus lateralis. Discussion The findings from the PEPC trial will provide new knowledge on the effects of high-load strength training on clinical and muscle cellular outcomes in prostate cancer patients during androgen deprivation therapy. Trial registration ClinicalTrials.gov: NCT0065822

Does Androgen Deprivation for Prostate Cancer Affect Normal Adaptation to Resistance Exercise?

Background: Loss of muscle mass and muscle function is a common side effect from androgen deprivation therapy (ADT) for prostate cancer (PCa). Here, we explored effects of heavy-load resistance training (RT) on lean body mass and muscle strength changes reported in randomized controlled trials (RCTs) among PCa patients on ADT and in healthy elderly men (HEM), by comparison of results in separate meta-analysis. Methods: RCTs were identified through databases and reference lists. Results: Seven RCTs in PCa patients (n = 449), and nine in HEM (n = 305) were included. The effects of RT in lean body mass change were similar among PCa patients (Standardized mean difference (SMD): 0.4, 95% CI: 0.2, 0.7) and HEM (SMD: 0.5, 95% CI: 0.2, 0.7). It is noteworthy that the within group changes showed different patterns in PCa patients (intervention: 0.2 kg; control: &minus;0.6 kg) and HEM (intervention: 1.2 kg; control: 0.2 kg). The effects of RT on change in muscle strength (measured as 1 RM) were similar between PCa patients and HEM, both for lower body- (PCa: SMD: 1.9, 95% CI: 1.2, 2.5; HEM: SMD: 2.2, 95% CI: 1.0, 3.4), and for upper body exercises (PCa: SMD: 2.0, 95% CI: 1.3, 2.7; HEM: SMD: 1.9, 95% CI: 1.3, 2.6). Conclusions: The effects of RT on lean body mass and 1 RM were similar in PCa patients on ADT and HEM, but the mechanism for the intervention effect might differ between groups. It seems that RT counteracts loss of lean body mass during ADT in PCa patients, as opposed to increasing lean body mass in HEM

Association of Genetically Predicted Insomnia With Risk of Sepsis: A Mendelian Randomization Study.

IMPORTANCE: Insomnia has been associated with altered inflammatory response as well as increased risk of infections and sepsis in observational studies. However, these studies are prone to bias, such as residual confounding. To further understand the potential causal association between insomnia and sepsis risk, a 2-sample Mendelian randomization (MR) approach should be explored. OBJECTIVE: To evaluate whether genetically predicted insomnia is associated with risk of sepsis. DESIGN, SETTING, AND PARTICIPANTS: Two-sample MR was performed to estimate the association between genetically predicted insomnia and sepsis risk. Data were obtained from a genome-wide association study identifying 555 independent genetic variants (R2 < 0.01) strongly associated with insomnia (P < 5 × 10-8). Sensitivity analyses were conducted to address bias due to pleiotropy and sample overlap, along with mediation analyses and sex-stratified analyses. The insomnia data set included 2.4 million individuals of European ancestry from the UK Biobank and 23andMe. For sepsis, 462 918 individuals of European ancestry from the UK Biobank were included. Data were extracted between February and December 2022 and analyzed between March 2022 and March 2023. EXPOSURE: Genetically predicted insomnia. MAIN OUTCOME AND MEASURE: Sepsis. RESULTS: There were 593 724 individuals with insomnia and 10 154 cases of sepsis. A doubling in the population prevalence of genetically predicted insomnia was associated with an odds ratio of 1.37 (95% CI, 1.19-1.57; P = 7.6 × 10-6) for sepsis. Sensitivity analyses supported this observation. One-third of the association between genetically predicted insomnia and risk of sepsis was mediated through a combination of cardiometabolic risk factors for sepsis (body mass index, type 2 diabetes, smoking, or cardiovascular disease; overall proportion, 35.2%; 95% CI, 5.1-76.9). The association between insomnia and sepsis was more pronounced among women compared with men (women: odds ratio, 1.44; 95% CI, 1.24-1.68; men: OR, 1.10; 95% CI, 0.86-1.40). CONCLUSIONS AND RELEVANCE: The concordance between these findings and previous observational studies supports that insomnia is potentially causally associated with the risk of sepsis. Thus, insomnia is a potential preventable risk factor of sepsis that should be further investigated, also in non-European populations

Association of Genetically Predicted Insomnia with Risk of Sepsis: A Mendelian Randomization Study

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Morphological, molecular and hormonal adaptations to early morning versus afternoon resistance training

It has been clearly established that maximal force and power is lower in the morning compared to noon or afternoon hours. This morning neuromuscular deficit can be diminished by regularly training in the morning hours. However, there is limited and contradictory information upon hypertrophic adaptations to time-of-day-specific resistance training. Moreover, no cellular or molecular mechanisms related to muscle hypertrophy adaptation have been studied with this respect. Therefore, the present study examined effects of the time-of-day-specific resistance training on muscle hypertrophy, phosphorylation of selected proteins, hormonal concentrations and neuromuscular performance. Twenty five previously untrained males were randomly divided into a morning group (n = 11, age 23 ± 2 yrs), afternoon group (n = 7, 24 ± 4 yrs) and control group (n = 7, 24 ± 3 yrs). Both the morning and afternoon group underwent hypertrophy-type of resistance training with 22 training sessions over an 11-week period performed between 07:30–08:30 h and 16:00–17:00 h, respectively. Isometric MVC was tested before and immediately after an acute loading exclusively during their training times before and after the training period. Before acute loadings, resting blood samples were drawn and analysed for plasma testosterone and cortisol. At each testing occasion, muscle biopsies from m. vastus lateralis were obtained before and 60 min after the acute loading. Muscle specimens were analysed for muscle fibre cross-sectional areas (CSA) and for phosphorylated p70S6K, rpS6, p38MAPK, Erk1/2, and eEF2. In addition, the right quadriceps femoris was scanned with MRI before and after the training period. The control group underwent the same testing, except for MRI, between 11:00 h and 13:00 h but did not train. Voluntary muscle strength increased significantly in both the morning and afternoon training group by 16.9% and 15.2 %, respectively. Also muscle hypertrophy occurred by 8.8% and 11.9% (MRI, p < 0.001) and at muscle fibre CSA level by 21% and 18% (p < 0.01) in the morning and afternoon group, respectively. No significant changes were found in controls within these parameters. Both pre- and post-training acute loadings induced a significant (p < 0.001) reduction in muscle strength in all groups, not affected by time of day or training. The post-loading phosphorylation of p70S6Thr421/Ser424 increased independent of the time of day in the pre-training condition, whereas it was significantly increased in the morning group only after the training period (p < 0.05). Phosphorylation of rpS6 and p38MAPK increased acutely both before and after training in a time-of-day independent manner (p < 0.05 at all occasions). Phosphorylation of p70S6Thr389, eEF2 and Erk1/2 did not change at any time point. No statistically significant correlations were found between changes in muscle fibre CSA, MRI and cell signalling data. Resting testosterone was not statistically different among groups at any time point. Resting cortisol declined significantly from pre- to post-training in all three groups (p < 0.05). In conclusion, similar levels of muscle strength and hypertrophy could be achieved regardless of time of the day in previously untrained men. However, at the level of skeletal muscle signalling, the extent of adaptation in some parameters may be time of day dependent.peerReviewe

Gestational age at birth and hospitalisations for infections among individuals aged 0–50 years in Norway:a longitudinal, register-based, cohort study

Summary Background: Preterm birth is associated with increased risk of childhood infections. Whether this risk persists into adulthood is unknown and limited information is available on risk patterns across the full range of gestational ages. Methods: In this longitudinal, register-based, cohort study, we linked individual-level data on all individuals born in Norway (January 01, 1967–December 31, 2016) to nationwide hospital data (January 01, 2008–December 31, 2017). Gestational age was categorised as 23–27, 28–31, 32–33, 34–36, 37–38, 39–41, and 42–44 completed weeks. The analyses were stratified by age at follow-up: 0–11 months and 1–5, 6–14, 15–29, and 30–50 years. The primary outcome was hospitalisation due to any infectious disease, with major infectious disease groups as secondary outcomes. Adjusted hospitalisation rate ratios (RRs) for any infection and infectious disease groups were estimated using negative binomial regression. Models were adjusted for year of birth, maternal age at birth, parity, and sex, and included an offset parameter adjusted for person-time at risk. Findings: Among 2,695,830 individuals with 313,940 hospitalisations for infections, we found a pattern of higher hospitalisation risk in lower gestational age groups, which was the strongest in childhood but still evident in adulthood. Comparing those born very preterm (28–31) and late preterm (34–36) to full-term (39–41 weeks), RRs (95% confidence interval) for hospitalisation for any infectious disease at ages 1–5 were 3.3 (3.0–3.7) and 1.7 (1.6–1.8), respectively. At 30–50 years, the corresponding estimates were 1.4 (1.2–1.7) and 1.2 (1.1–1.3). The patterns were similar for the infectious disease groups, including bacterial and viral infections, respiratory tract infections (RTIs), and infections not attributable to RTIs. Interpretation: Increasing risk of hospitalisations for infections in lower gestational age groups was most prominent in children but still evident in adolescents and adults. Possible mechanisms and groups that could benefit from vaccinations and other prevention strategies should be investigated. Funding: St. Olav’s University Hospital and Norwegian University of Science and Technology, Norwegian Research Council, Liaison Committee for education, research and innovation in Central Norway, European Commission, Academy of Finland, Sigrid Jusélius Foundation, Foundation for Pediatric Research, and Signe and Ane Gyllenberg Foundation

Reporting of resistance training dose, adherence, and tolerance in exercise oncology

Purpose: While general guidelines (such as CONSORT or Consensus on Exercise Reporting Template) exist to enhance the reporting of exercise interventions in the field of exercise science, there is inadequate detail facilitating the standardized reporting of resistance training adherence in the oncology setting. The purpose of this study was to apply a novel method to report resistance training dose, adherence, and tolerance in patients with cancer. Methods: A total of 47 prostate cancer patients (70.1 ± 8.9 yr, body mass index, 28.6 ± 4.0) with bone metastatic disease completed an exercise program for 12 wk. We assessed traditional metrics of adherence (attendance and loss to follow-up), in addition to novel proposed metrics (exercise-relative dose intensity, dose modification, and exercise interruption). Total training volume in kilograms (repetitions x sets x training load (weight)) was calculated for each patient. Results: Attendance assessed from traditional metrics was 79.5% ± 17.0% and four patients (9%) were lost to follow-up. The prescribed and actual cumulative total dose of resistance training was 139,886 ± 69,150 kg and 112,835 ± 83,499 kg, respectively, with a mean exercise-relative dose intensity of 77.4% ± 16.6% (range: 19.4% –99.4%). Resistance training was missed (1–2 consecutive sessions) or interrupted (missed ≥3 consecutive sessions) in 41 (87%) and 24 (51%) participants, respectively. Training dose was modified (reduction in sets, repetitions, or weight) in 40 (85%) of patients. Importantly, using attendance as a traditional metric of adherence, these sessions would have all counted as adherence to the protocol. Conclusions: Traditional reporting metrics of resistance training in exercise oncology may overestimate exercise adherence. Our proposed metrics to capture resistance training dose, adherence, and tolerance may have important applications for future studies and clinical practice