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Elisabeth C van der Slikke,1 Lise FE Beumeler,2,3 Madlene Holmqvist,4 Adam Linder,4 Robert T Mankowski,5 Hjalmar R Bouma1,6 1Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, 9713GZ, the Netherlands; 2Department of Intensive Care, Medical Centre Leeuwarden, Leeuwarden, 8934AD, the Netherlands; 3Department of Sustainable Health, Campus Fryslân, University of Groningen, Groningen, 8911 CE, the Netherlands; 4Department of Infection Medicine, Skåne University Hospital Lund, Lund, 221 84, Sweden; 5Department of Physiology and Aging, University of Florida, Gainesville, FL, 32610, USA; 6Department of Internal Medicine, University of Groningen, University Medical Center Groningen, Groningen, 9713GZ, the NetherlandsCorrespondence: Hjalmar R Bouma, Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, P.O. Box 30.001, EB70, Groningen, 9700 RB, the Netherlands, Tel +31 (0) 50 361 7870, Email h.r.bouma@umcg.nlAbstract: Sepsis is a global health challenge, with over 49 million cases annually. Recent medical advancements have increased in-hospital survival rates to approximately 80%, but the escalating incidence of sepsis, owing to an ageing population, rise in chronic diseases, and antibiotic resistance, have also increased the number of sepsis survivors. Subsequently, there is a growing prevalence of “post-sepsis syndrome” (PSS). This syndrome includes long-term physical, medical, cognitive, and psychological issues after recovering from sepsis. PSS puts survivors at risk for hospital readmission and is associated with a reduction in health- and life span, both at short and long term, after hospital discharge. Comprehensive understanding of PSS symptoms and causative factors is vital for developing optimal care for sepsis survivors, a task of prime importance for clinicians. This review aims to elucidate our current knowledge of PSS and its relevance in enhancing post-sepsis care provided by clinicians.Keywords: post-sepsis syndrome, sepsis, long-term outcome

Ageing is an escalating global health issue, with the World Health Organization (WHO) reporting that one in six individuals will be 60 years or older by the year 2030. Therefore, understanding the mechanisms of complex biological ageing processes and associated healthcare challenges has become increasingly important. Intrinsic capacity (IC), defined by WHO as the composite of all physical and mental capacities an individual possesses, can be used as a proxy for defining healthy ageing. IC has five key components: locomotion, cognition, psychological, sensory, and vitality capacity (VC). This review paper specifically focuses on exercise as an effective tool to preserve VC in ageing populations. The physiological domains of VC discussed include energy and metabolism, neuromuscular function, immune and stress response, mitochondrial function, and the methylation clock. Additionally, we highlight potential outcome measures for assessing each of these domains. This review also covers areas of focus for future research and possible interventions. We ultimately conclude that ageing is a complex, multifaceted process resulting in deficits across multiple VC components. However, regular exercise is capable of producing physiological adaptations that may be beneficial in the context of healthy ageing and improving or preserving the status of VC components., (© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: While sepsis, an exaggerated response to infection, can affect people of all age groups, it is more prevalent in middle-aged and older adults. Older adults suffer worse short-term and long-term outcomes than younger patients. Older sepsis survivors are commonly discharged to long-term acute care facilities, where they often die within 1 year. Those who return home from the hospital lose the momentum of physical function improvement after early inpatient rehabilitation, and often face exacerbation of comorbidities and decline in physical function. Additionally, patients who are discharged home often live at distant locations and are not able to commute to rehabilitation centers due to their poor health status. Therefore, remotely delivered exercise interventions tailored to this population hold promise to improve physical function safely and effectively after sepsis. However, this type of intervention has yet to be tested in this population., Objective: This study aims to assess the safety, feasibility, and ease of recruitment and retention of participants for a remotely delivered physical activity intervention for improving physical function in middle-aged and older sepsis survivors., Methods: The proposed intervention will be delivered through a digital health platform that comprises a patient-facing mobile app and a 12-week physical activity program specifically designed for middle-aged and older sepsis survivors with poor health status who may face challenges participating in traditional out-patient or community-based exercise interventions. This study is ongoing and plans to enroll 40 sepsis survivors aged 55 years and older who will be randomized to either a remotely delivered exercise intervention group or a control group (electronic health diary). Both groups will use a tablet containing the Health in Motion app (Blue Marble Health). The intervention group will receive a clinician-designed personalized avatar-guided home exercise program and reminders while the control group will self-report daily activities using the in-app health diary feature., Results: This study is the first to use a home-based, remotely monitored 12-week exercise program to improve physical function in sepsis survivors. This study will evaluate the safety, feasibility, and efficacy, providing the necessary knowledge to design and calculate power for future larger trials., Conclusions: This study will provide important information for planning a future randomized clinical trial to test the efficacy of a remotely delivered exercise intervention in this high-risk population., Trial Registration: ClinicalTrials.gov NCT05568511; https://clinicaltrials.gov/study/NCT05568511., International Registered Report Identifier (irrid): DERR1-10.2196/60270., (©Rola S Zeidan, Margaret K Ohama, Natalia Evripidou, Stephen D Anton, Laith L Hamed, Yi Lin, Christiaan Leeuwenburgh, Faheem W Guirguis, Philip A Efron, Sheryl Flynn, Barbara Smith, Rhonda Bacher, Naveen Bakarasan, Juan Sarmiento Delgado, Robert T Mankowski. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 17.10.2024.)

Objective: To evaluate the persistence of intestinal microbiome dysbiosis and gut-plasma metabolomic perturbations following severe trauma or sepsis weeks after admission in patients experiencing chronic critical illness (CCI)., Summary: Trauma and sepsis can lead to gut dysbiosis and alterations in the plasma and fecal metabolome. However, the impact of these perturbations and correlations between gut dysbiosis and the plasma metabolome in chronic critical illness have not been studied., Methods: A prospective observational cohort study was performed with healthy subjects, severe trauma patients, and patients with sepsis residing in an intensive care unit for 2 to 3 weeks. A high-throughput multi-omics approach was utilized to evaluate the gut microbial and gut-plasma metabolite responses in critically ill trauma and sepsis patients 14 to 21 days after intensive care unit admission., Results: Patients in the sepsis and trauma cohorts demonstrated strikingly depleted gut microbiome diversity, with significant alterations and specific pathobiome patterns in the microbiota composition compared to healthy subjects. Further subgroup analyses based on sex revealed resistance to changes in microbiome diversity among female trauma patients compared to healthy counterparts. Sex--specific changes in fecal metabolites were also observed after trauma and sepsis, while plasma metabolite changes were similar in both males and females., Conclusions: Dysbiosis induced by trauma and sepsis persists up to 14 to 21 days after onset and is sex-specific, underscoring the implication of pathobiome and entero-septic microbial-metabolite perturbations in post-sepsis and posttrauma chronic critical illness. This indicates resilience to infection or injury in females' microbiome and should inform and facilitate future precision/personalized medicine strategies in the intensive care unit., Competing Interests: J.A.M. and L.S.K. are supported by a postgraduate training grant NIH NIGMS T32 GM-008721. R.N. acknowledges funding from the Florida Department of Health (FL DOH #23A02 and #24A05), the United States Department of Agriculture (USDA-ARS #440658), the Infectious Diseases Society of America (IDSA), the Florida State University Council on Research & Creativity (FSU-CRC), and the FSU College of Education, Health, and Human Sciences (FSU-CEHHS). The remaining authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Iron plays a crucial role in many physiological processes, including oxygen transport, bioenergetics, and immune function. Iron is assimilated from food and also recycled from senescent red blood cells. Iron exists in two dietary forms: heme (animal based) and non-heme (mostly plant based). The body uses iron for metabolic purposes, and stores the excess mainly in splenic and hepatic macrophages. Physiologically, iron excretion in humans is inefficient and not highly regulated, so regulation of intestinal absorption maintains iron homeostasis. Iron losses occur at a steady rate via turnover of the intestinal epithelium, blood loss, and exfoliation of dead skin cells, but overall iron homeostasis is tightly controlled at cellular and systemic levels. Aging can have a profound impact on iron homeostasis and induce a dyshomeostasis where iron deficiency or overload (sometimes both simultaneously) can occur, potentially leading to several disorders and pathologies. To maintain physiologically balanced iron levels, reduce risk of disease, and promote healthy aging, it is advisable for older adults to follow recommended daily intake guidelines and periodically assess iron levels. Clinicians can evaluate body iron status using different techniques but selecting an assessment method primarily depends on the condition being examined. This review provides a comprehensive overview of the forms, sources, and metabolism of dietary iron, associated disorders of iron dyshomeostasis, assessment of iron levels in older adults, and nutritional guidelines and strategies to maintain iron balance in older adults., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Sepsis and trauma are known to disrupt gut bacterial microbiome communities, but the impacts and perturbations in the fungal (mycobiome) community after severe infection or injury, particularly in patients experiencing chronic critical illness (CCI), remain unstudied., Methods: We assess persistence of the gut mycobiome perturbation (dysbiosis) in patients experiencing CCI following sepsis or trauma for up to two-to-three weeks after intensive care unit hospitalization., Results: We show that the dysbiotic mycobiome arrays shift toward a pathobiome state, which is more susceptible to infection, in CCI patients compared to age-matched healthy subjects. The fungal community in CCI patients is largely dominated by Candida spp; while, the commensal fungal species are depleted. Additionally, these myco-pathobiome arrays correlate with alterations in micro-ecological niche involving specific gut bacteria and gut-blood metabolites., Conclusions: The findings reveal the persistence of mycobiome dysbiosis in both sepsis and trauma settings, even up to two weeks post-sepsis and trauma, highlighting the need to assess and address the increased risk of fungal infections in CCI patients., (© 2024. The Author(s).)

By definition, aging is a natural, gradual and continuous process. On the other hand, frailty reflects the increase in vulnerability to stressors and shortens the time without disease (health span) while longevity refers to the length of life (lifespan). The average life expectancy has significantly increased during the last few decades. A longer lifespan has been accompanied by an increase in frailty and decreased independence in older adults, with major differences existing between men and women. For example, women tend to live longer than men but also experience higher rates of frailty and disability. Sex differences prevent optimization of lifestyle interventions and therapies to effectively prevent frailty. Sex differences in frailty and aging are rooted in a complex interplay between uncontrollable (genetic, epigenetic, physiological), and controllable factors (psychosocial and lifestyle factors). Thus, understanding the underlying causes of sex differences in frailty and aging is essential for developing personalized interventions to promote healthy aging and improve quality of life in older men and women. In this review, we have discussed the key contributors and knowledge gaps related to sex differences in aging and frailty., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Mechanical ventilation during cardiothoracic surgery is life-saving but can lead to ventilator-induced diaphragm dysfunction (VIDD) and prolong ventilator weaning and hospital length of stay. Intraoperative phrenic nerve stimulation may preserve diaphragm force production to offset VIDD; we also investigated changes in mitochondrial function after stimulation. During cardiothoracic surgeries ( n = 21), supramaximal, unilateral phrenic nerve stimulation was performed every 30 min for 1 min. Diaphragm biopsies were collected after the last stimulation and analyzed for mitochondrial respiration in permeabilized fibers and protein expression and enzymatic activity of biomarkers of oxidative stress and mitophagy. Patients received, on average, 6.2 ± 1.9 stimulation bouts. Stimulated hemidiaphragms showed lower leak respiration, maximum electron transport system (ETS) capacities, oxidative phosphorylation (OXPHOS), and spare capacity compared with unstimulated sides. There were no significant differences between mitochondrial enzyme activities and oxidative stress and mitophagy protein expression levels. Intraoperative phrenic nerve electrical stimulation led to an acute decrease of mitochondrial respiration in the stimulated hemidiaphragm, without differences in biomarkers of mitophagy or oxidative stress. Future studies warrant investigating optimal stimulation doses and testing post-operative chronic stimulation effects on weaning from the ventilator and rehabilitation outcomes.

Objectives: Individuals with prior cancer diagnosis are more likely to have low muscle mass (LMM) than their cancer-free counterparts. Understanding the effects of LMM on the prognosis of cancer survivors can be clinically important. The aim of this study was to investigate whether risks for all-cause and cardiovascular disease (CVD)-specific mortality differ by status of LMM in cancer survivors and a matched cohort without cancer history., Methods: We used cohort data from the 1999-2006 and 2011-2014 National Health and Nutrition Examination Survey. Participants included 946 adults surviving for ≥1 since cancer diagnosis and a matched cohort (by age, sex, and race) without cancer history (N = 1857). LMM was defined by appendicular lean mass and body height (men <7.26 kg/m 2 , women <5.45 kg/m 2 ). Death was ascertained via the National Death Index and cause of death was assessed via International Classification of Diseases, Tenth Revision. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratio (aHR) and 95% confidence interval (CI) of LMM., Results: The mean age of cancer survivors and matched cohort was 60.6 y (SD 15) and 60.2 y (SD 14.9), respectively. The median follow-up was 10.5 y for survivors and 10.9 y for matched cohort. Overall, 22.2% of cancer survivors and 19.7% of the matched cohort had LMM, respectively. In all, 321 survivors (33.9%) and 495 participants (26.7%) in the matched cohort died during follow-up. CVD-specific deaths were identified in 58 survivors (6.1%) and 122 participants in the matched cohort (6.6%). The multivariable Cox model suggested that LMM was positively associated with all-cause (aHR, 1.73; 95% CI, 1.31-2.29) and CVD-specific (aHR, 2.13; 95% CI, 1.14-4.00) mortality in cancer survivors. The associations between LMM and risk for all-cause (aHR, 1.24; 95% CI, 0.98-1.56) and CVD-specific (aHR, 1.21; 95% CI, 0.75-1.93) mortality were not statistically significant in the matched cohort., Conclusion: Cancer survivors with LMM have an increased risk for all-cause and CVD-specific mortality. This increase appears to be larger than that in counterparts without cancer history., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Altered mitochondrial quality and function in muscle may be involved in age-related physical function decline. The role played by the autophagy-lysosome system, a major component of mitochondrial quality control (MQC), is incompletely understood. This study was undertaken to obtain initial indications on the relationship between autophagy, mitophagy, and lysosomal markers in muscle and measures of physical performance and lower extremity tissue composition in young and older adults. Twenty-three participants were enrolled, nine young (mean age: 24.3 ± 4.3 years) and 14 older adults (mean age: 77.9 ± 6.3 years). Lower extremity tissue composition was quantified volumetrically by magnetic resonance imaging and a tissue composition index was calculated as the ratio between muscle and intermuscular adipose tissue volume. Physical performance in older participants was assessed via the Short Physical Performance Battery (SPPB). Protein levels of the autophagy marker p62, the mitophagy mediator BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), the lysosomal markers transcription factor EB, vacuolar-type ATPase, and lysosomal-associated membrane protein 1 were measured by Western immunoblotting in vastus lateralis muscle biopsies. Older adults had smaller muscle volume and lower tissue composition index than young participants. The protein content of p62 and BNIP3 was higher in older adults. A negative correlation was detected between p62 and BNIP3 and the tissue composition index. p62 and BNIP3 were also related to the performance on the 5-time sit-to-stand test of the SPPB. Our results suggest that an altered expression of markers of the autophagy/mitophagy-lysosomal system is related to deterioration of lower extremity tissue composition and muscle dysfunction. Additional studies are needed to clarify the role of defective MQC in human muscle aging and identify novel biological targets for drug development.

Background: Natural dietary compounds that can modulate the inflammation process have the potential to improve physical function through a number of biological pathways, and thus may represent an alternative approach to avert functional decline compared to more time-burdening lifestyle interventions. In this pilot trial, we tested the feasibility and explored the effect of a nutritional compound, Curcumin C3 Complex® for improving physical function and muscle strength in moderately functioning older adults with low-grade inflammation., Methods: Moderately functioning (short physical performance battery, SPPB <10) and sedentary older adults (>65 years) with low-grade systemic inflammation (c-reactive protein >1mg/dL) were randomized to receive Curcumin C3 Complex® (n=9) (1000mg/day) or placebo (n=8) groups for 12 weeks. All participants (age range: 66-94 years, 8 females and 9 males) underwent functional testing (SPPB and walking speed by the 400-meter walk test) and lower-limb strength (knee flexion and extension peak torque by the Biodex test) at baseline and 12 weeks. Venous blood was collected at baseline, 4, 8 and 12 weeks for safety blood chemistry analyses and biomarkers of inflammation., Results: A total of 17 participants were randomized and completed the study. Adherence was high (> 90%) and there were no adverse events reported or abnormal blood chemistries reported. Based on effect sizes, participants in the Curcumin C3 Complex® group demonstrated large effect sizes in the SPPB (Cohen's effect size d=0.75) and measures of knee extension (d=0.69) and flexion peak torque (d=0.82). Effect sizes for galectin-3 (d=-0.31) (larger decrease) and interleukin-6 (d=0.38) (smaller increase) were small in the Curcumin C3 Complex® group compared to placebo., Conclusion: This pilot trial suggests that there were no difficulties with recruitment, adherence and safety specific to the study protocol. Preliminary findings warrant a Phase IIb clinical trial to test the effect of Curcumin C3 Complex® on physical function and muscle strength in older adults at risk for mobility disability., Competing Interests: none.

Background: Sepsis-induced gut microbiome alterations contribute to sepsis-related morbidity and mortality. Given evidence for improved postsepsis outcomes in females compared with males, we hypothesized that female mice maintain microbiota resilience versus males., Methods: Mixed-sex C57BL/6 mice underwent cecal ligation and puncture (CLP) with antibiotics, saline resuscitation, and daily chronic stress and were compared with naive (nonsepsis/no antibiotics) controls. For this work, the results of young (3-5 months) and old (18-22 months) adult mice were analyzed by sex, independent and dependent of age. Mice were sacrificed at days 7 and 14, and 16S rRNA gene sequencing was performed on fecal bacterial DNA. α and β diversity were determined by Shannon index and Bray-Curtis with principal coordinate analysis, respectively. False discovery rate (FDR) correction was implemented to account for potential housing effect., Results: In control mice, there was no difference in α or β diversity between male and female mice (FDR, 0.76 and 0.99, respectively). However, male mice that underwent CLP with daily chronic stress had a decrease in microbiota α diversity at 7 days post-CLP (Shannon FDR, 0.005), which was sustained at 14 days post-CLP (Shannon FDR, 0.001), compared with baseline. In addition, male mice maintained differences in β diversity even at day 14 compared with controls (FDR, <0.0001). In contrast, female mice had a decreased microbiota α diversity (Shannon FDR, 0.03) and β diversity (FDR, 0.02) 7 days post-CLP but recovered their α and β diversity by post-CLP day 14 (Shannon FDR, 0.5, and FDR, 0.02, respectively). Further analysis of females revealed that only young female mice were not different (β diversity) post-CLP day 14 to controls., Conclusion: Although sepsis-induced perturbations of the intestinal microbiota occur initially in both male and female C57BL/6 mice, females demonstrate different microbiota by day 14. This may be seen primarily in younger females. This difference in recovery may play a role in outcome differences between sexes after sepsis., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Surgery of Trauma.)

Background: Hospital deaths after sepsis have decreased substantially and most young adult survivors rapidly recover (RAP). However, many older survivors develop chronic critical illness (CCI) with poor long-term outcomes. The etiology of CCI is multifactorial and the relative importance remains unclear. Sepsis is caused by a dysregulated immune response and biomarkers reflecting a persistent inflammation, immunosuppression, and catabolism syndrome (PICS) have been observed in CCI after sepsis. Therefore, the purpose of this study was to compare serial PICS biomarkers in (i) older (vs young) adults and (ii) older CCI (vs older RAP) patients to gain insight into underlying pathobiology of CCI in older adults., Method: Prospective longitudinal study with young (≤45 years) and older (≥65 years) septic adults, who were characterized by (i) baseline predisposition, (ii) hospital outcomes, (iii) serial Sequential Organ Failure Assessment (SOFA) organ dysfunction scores over 14 days, (iv) Zubrod Performance status at 3-, 6-, and 12-month follow-up, and (v) mortality over 12 months, was conducted. Serial blood samples over 14 days were analyzed for selected biomarkers reflecting PICS., Results: Compared to the young, more older adults developed CCI (20% vs 42%) and had markedly worse serial SOFA scores, performance status, and mortality over 12 months. Additionally, older (vs young) and older CCI (vs older RAP) patients had more persistent aberrations in biomarkers reflecting inflammation, immunosuppression, stress metabolism, lack of anabolism, and antiangiogenesis over 14 days after sepsis., Conclusion: Older (vs young) and older CCI (vs older RAP) patient subgroups demonstrate early biomarker evidence of the underlying pathobiology of PICS., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Abstract: Sepsis is currently defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. The skeletal muscle system is among the host organ systems compromised by sepsis. The resulting neuromuscular dysfunction and impaired regenerative capacity defines sepsis-induced myopathy and manifests as atrophy, loss of strength, and hindered regeneration after injury. These outcomes delay recovery from critical illness and confer increased vulnerability to morbidity and mortality. The mechanisms underlying sepsis-induced myopathy, including the potential contribution of peripheral organs, remain largely unexplored. The gut microbiome is an immunological and homeostatic entity that interacts with and controls end-organ function, including the skeletal muscle system. Sepsis induces alterations in the gut microbiota composition, which is globally termed a state of "dysbiosis" for the host compared to baseline microbiota composition. In this review, we critically evaluate existing evidence and potential mechanisms linking sepsis-induced myopathy with gut microbiota dysbiosis., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 by the Shock Society.)

Background: Vitamin D insufficiency contributes to muscle weakness and a higher risk of falls in older adults., Objectives: This study explored the impact of vitamin D supplementation on self-reported falls and physical function in older adults with low vitamin D levels and a recent fall history., Materials and Methods: Twenty-five older adults ≥ 70 years with two or more falls during the past year, low vitamin D blood levels (≥10 ng/ml and < 30 ng/mL), and slow gait speed (1.2 m/s) participated in a 6-month vitamin D supplementation (800 IU/day) study. A modified version of the Morse Fall Scale questionnaire was used to assess frequency of falls over one-year prior to study enrollment. Functional outcomes (short physical performance battery, handgrip strength, gait Timed Up and Go, and six-minute walk), and vitamin D levels were assessed at baseline and 6-month follow-up., Results: Based on diaries and pill counts, participants were generally adherent to the intervention (6 of 7 days per week). Supplementation with 800 IU/day of vitamin D for 6 months increased blood vitamin D levels from 23.25±4.8 ng/ml to 29.13±6.9 ng/ml (p<0.001). Self-reported number of falls decreased from an average of 3.76 ± 2.2 falls in one-year to 0.76 plusmn; 1.4 falls (p <0.0001) over the 6-month intervention. No changes in functional outcome measures were observed., Conclusions: Vitamin D supplementation at the currently recommended dose of 800 IU/day increased blood vitamin D levels and reduced frequency of falls in older adults with low vitamin D levels and a recent fall history., Competing Interests: The authors declare no conflict of interest.

Spexin (SPX) is a 14-amino acid neuropeptide, discovered recently using bioinformatic techniques. It is encoded by the Ch12:orf39 gene that is widely expressed in different body tissues/organs across species, and secreted into systemic circulation. Recent reports have highlighted a potentially important regulatory role of SPX in obesity and related comorbidities. SPX is also ubiquitously expressed in human tissues, including white adipose tissue. The circulating concentration of SPX is significantly lower in individuals with obesity compared to normal weight counterparts. SPX's role in obesity appears to be related to various factors, such as the regulation of energy expenditure, appetite, and eating behaviors, increasing locomotion, and inhibiting long-chain fatty acid uptake into adipocytes. Recent reports have also suggested SPX's relationship with novel biomarkers of cardiovascular disease (CVD) and glucose metabolism and evoked the potential role of SPX as a key biomarker/player in the early loss of cardiometabolic health and development of CVD and diabetes later in life. Data on age-related changes in SPX and SPX's response to various interventions are also emerging. The current review focuses on the role of SPX in obesity and related comorbidities across the life span, and its response to interventions in these conditions. It is expected that this article will provide new ideas for future research on SPX and its metabolic regulation, particularly related to cardiometabolic diseases., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Sepsis survivors experience a persistent myopathy characterized by skeletal muscle weakness, atrophy, and an inability to repair/regenerate damaged or dysfunctional myofibers. The origins and mechanisms of this persistent sepsis-induced myopathy are likely complex and multifactorial. Nevertheless, the pathobiology is thought to be triggered by the interaction between circulating pathogens and impaired muscle metabolic status. In addition, while in the hospital, septic patients often experience prolonged periods of physical inactivity due to bed rest, which may exacerbate the myopathy. Physical rehabilitation emerges as a potential tool to prevent the decline in physical function in septic patients. Currently, there is no consensus regarding effective rehabilitation strategies for sepsis-induced myopathy. The optimal timing to initiate the rehabilitation intervention currently lacks consensus as well. In this review, we summarize the evidence on the fundamental pathobiological mechanisms of sepsis-induced myopathy and discuss the recent evidence on in-hospital and post-discharge rehabilitation as well as other potential interventions that may prevent physical disability and death of sepsis survivors.

Background: Older adults have worse outcomes after sepsis than young adults. Additionally, alterations of the gut microbiota have been demonstrated to contribute to sepsis-related mortality. We sought to determine if there were alterations in the gut microbiota with a novel sepsis model in old adult mice, which enter a state of persistent inflammation, immunosuppression, and catabolism (PICS), as compared with young adult mice, which recover with the sepsis model., Methods: Mixed sex old (∼20 mo) and young (∼4 mo) C57Bl/6J mice underwent cecal ligation and puncture with daily chronic stress (CLP+DCS) and were compared with naive age-matched controls. Mice were sacrificed at CLP+DCS day 7 and feces collected for bacterial DNA isolation. The V3-V4 hypervariable region was amplified, 16S rRNA gene sequencing performed, and cohorts compared. α-Diversity was assessed using Chao1 and Shannon indices using rarefied counts, and β-diversity was assessed using Bray-Curtis dissimilarity., Results: Naive old adult mice had significantly different α and β-diversity compared with naive adult young adult mice. After CLP+DCS, there was a significant shift in the α and β-diversity (FDR = 0.03 for both) of old adult mice (naive vs. CLP+DCS). However, no significant shift was displayed in the microbiota of young mice that underwent CLP+DCS in regards to α-diversity (FDR = 0.052) and β-diversity (FDR = 0.12), demonstrating a greater overall stability of their microbiota at 7 days despite the septic insult. The taxonomic changes in old mice undergoing CLP+DCS were dominated by decreased abundance of the order Clostridiales and genera Oscillospira., Conclusion: Young adult mice maintain an overall microbiome stability 7 days after CLP+DCS after compared with old adult mice. The lack of microbiome stability could contribute to PICS and worse long-term outcomes in older adult sepsis survivors. Further studies are warranted to elucidate mechanistic pathways and potential therapeutics., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

With the ever-expanding population of patients infected with SARS-CoV-2, we are learning more about the immediate and long-term clinical manifestations of coronavirus disease 2019 (COVID-19). Ischemic stroke (IS) is now one of the well-documented additional clinical manifestations of COVID-19. Most COVID-19 related IS cases have been categorized as cryptogenic or embolic stroke of undetermined source (ESUS), which are most often suspected to have an undiagnosed cardioembolic source. COVID-19 is known to also cause cardiac dysfunction, heart failure, and atrial arrhythmias (AA), but the long-term impact of this cardiac dysfunction on stroke incidence is unknown. With millions afflicted with COVID-19 and the ever-rising infection rate, it is important to consider the potential long-term impact of COVID-19 on future IS incidence. Accomplishing these goals will require novel strategies that allow for diagnosis, data capture, and prediction of future IS risk using tools that are adaptable to the evolving clinical challenges in patient care delivery and research., Competing Interests: None for any of the authors., (© 2021 The Authors.)

Aging-related changes to biological structures such as cardiovascular and musculoskeletal systems contribute to the development of comorbid conditions including cardiovascular disease and frailty, and ultimately lead to premature death. Although, frail older adults often demonstrate both cardiovascular and musculoskeletal comorbidities, the etiology of sarcopenia, and especially the contribution of cardiovascular aging is unclear. Aging-related vascular calcification is prevalent in older adults and is a known risk factor for cardiovascular disease and death. The effect vascular calcification has on function during aging is not well understood. Emerging findings suggest vascular calcification can impact skeletal muscle perfusion, negatively affecting nutrient and oxygen delivery to skeletal muscle, ultimately accelerating muscle loss and functional decline. The present review summarizes existing evidence on the biological mechanisms linking vascular calcification with sarcopenia during aging., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Older patients experience a decline in their physiologic reserves as well as chronic low-grade inflammation named "inflammaging." Both of these contribute significantly to aging-related factors that alter the acute, subacute, and chronic response of these patients to critical illness, such as sepsis. Unfortunately, this altered response to stressors can lead to chronic critical illness followed by dismal outcomes and death. The primary goal of this review is to briefly highlight age-specific changes in physiologic systems majorly affected in critical illness, especially because it pertains to sepsis and trauma, which can lead to chronic critical illness and describe implications in clinical management., Competing Interests: Disclosure The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: To evaluate the safety and feasibility of combining exercise (EX) and resveratrol to treat older adults with physical function limitations., Methods: Three-arm, two-site pilot randomized, controlled trial (RCT) for community-dwelling adults (N = 60), 71.8 ± 6.3 years of age with functional limitations. Participants were randomized to receive either 12 weeks of (1) EX + placebo [EX0], (2) EX + 500 mg/day resveratrol [EX500], or (3) EX + 1000 mg/day resveratrol [EX1000]. EX consisted of two sessions a week for 12 weeks of center-based walking and whole-body resistance training. Safety was assessed through adverse events and feasibility through exercise session and supplement (placebo, or resveratrol) protocol adherence. Outcome measures included a battery of indices of physical function as well as skeletal muscle mitchondrial function. Data were adjusted for age and gender using the Intent-To-Treat approach., Results: Adverse event frequency and type were similar between groups (n = 8 EX0, n = 12 EX500, and n = 7 EX1000). Overall, 85% of participants met the supplement adherence via pill counts while 82% met the exercise session adherence. Adjusted within group mean differences (95% confidence interval) from week 0 to 12 for gait speed ranged from -0.04 (EX0: -0.1, 0.03) m/s to 0.04 (EX1000: -0.02, 0.11) and the six-minute walk test mean differences were 9.45 (EX0: -9.02, 27.7), 22.9 (EX500: 4.18, 41.6), and 33.1 (EX1000: 13.8, 52.4) meters. Unadjusted mean differences for citrate synthase were -0.80 (EX0: -15.45, 13.84), -1.38 (EX500: -12.16, 9.39), and 7.75 (EX1000: -4.68, 20.18) mU/mg. COX activity mean within group changes ranged from -0.05 (EX0) to 0.06 (EX500) k/s/mg. Additional outcomes are detailed in the text., Conclusion: The pilot RCT indicated that combined EX + resveratrol was safe and feasible for older adults with functional limitations and may improve skeletal muscle mitochondrial function and mobility-related indices of physical function. A larger trial appears warranted and is needed to formally test these hypotheses., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial-iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA 4977 ) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope ( 56 Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA 4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability.

Aging is the primary risk factor for functional decline; thus, understanding and preventing disability among older adults has emerged as an important public health challenge of the 21st century. The science of gerontology - or geroscience - has the practical purpose of "adding life to the years." The overall goal of geroscience is to increase healthspan, which refers to extending the portion of the lifespan in which the individual experiences enjoyment, satisfaction, and wellness. An important facet of this goal is preserving mobility, defined as the ability to move independently. Despite this clear purpose, this has proven to be a challenging endeavor as mobility and function in later life are influenced by a complex interaction of factors across multiple domains. Moreover, findings over the past decade have highlighted the complexity of walking and how targeting multiple systems, including the brain and sensory organs, as well as the environment in which a person lives, can have a dramatic effect on an older person's mobility and function. For these reasons, behavioral interventions that incorporate complex walking tasks and other activities of daily living appear to be especially helpful for improving mobility function. Other pharmaceutical interventions, such as oxytocin, and complementary and alternative interventions, such as massage therapy, may enhance physical function both through direct effects on biological mechanisms related to mobility, as well as indirectly through modulation of cognitive and socioemotional processes. Thus, the purpose of the present review is to describe evolving interventional approaches to enhance mobility and maintain healthspan in the growing population of older adults in the United States and countries throughout the world. Such interventions are likely to be greatly assisted by technological advances and the widespread adoption of virtual communications during and after the COVID-19 era., (Copyright © 2020. Published by Elsevier Inc.)

Objectives: Sepsis has been called a "disease of the elderly," and as in-hospital mortality has decreased, more sepsis survivors are progressing into poorly characterized long-term outcomes. The purpose of this study was to describe the current epidemiology of sepsis in older adults compared with middle-aged and young adults., Design: Prospective longitudinal study with young (≤45 years), middle-aged (46-64 years), and older (≥65 years) patient groups., Setting: University tertiary medical center., Participants: A total of 328 adult surgical intensive care unit (ICU) sepsis patients., Measurements: Patients were characterized by (1) baseline demographics and predisposition, (2) septic event, (3) hospital outcomes and discharge disposition, (4) 12-month mortality, and (5) Zubrod Performance Status, physical function (Short Physical Performance Battery and handgrip strength), and cognitive function (Hopkins Verbal Learning Test, Controlled Oral Word Association, and Mini-Mental Status Examination) at 3-, 6-, and 12-month follow-up. Loss to follow-up was due to death (in 68), consent withdrawal (in 32), and illness and scheduling difficulties: month 3 (in 51), month 6 (in 29), and month 12 (in 20)., Results: Compared with young and middle-aged patients, older patients had (1) significantly more comorbidities at presentation (eg, chronic renal disease 6% vs 12% vs 21%), intra-abdominal infections (14% vs 25% vs 37%), septic shock (12% vs 25% vs 36%), and organ dysfunctions; (2) higher 30-day mortality (6% vs 4% vs 17%) and fewer ICU-free days (median = 25 vs 23 vs 20); (3) more progression into chronic critical illness (22% vs 34% vs 42%) with higher poor disposition discharge to non-home destinations (19% vs 40% vs 62%); (4) worse 12-month mortality (11% vs 14% vs 33%); and (5) poorer Zubrod Performance Status and objectively measured physical and cognitive functions with only slight improvement over 12-month follow-up., Conclusion: Compared with younger patients, older sepsis survivors suffer both a higher persistent disability burden and 12-month mortality., (© 2020 The American Geriatrics Society.)

Previous studies have found an inverse relation between serum concentrations of interleukin (IL)-6 and physical performance in seniors, however this was limited to higher functioning older adults with low to moderate levels of inflammation. We explored the consistency of this association in a cohort of mobility limited older adults with chronic low-grade inflammation. This study included 289 participants (≥ 70 years old) with IL-6 level between 2.5 and 30 pg/mL and a walking speed < 1.0 m/sec from the ENRGISE Pilot study. Physical performance was assessed using the short physical performance battery (SPPB), usual gait speed over 400 m, grip strength, and knee extensor and flexor strength measured by isokinetic dynamometry at 60 and 180°/sec. There was a significant inverse correlation between log IL-6 and knee extensor strength at 60°/sec (r= -0.20, p = 0.002), at 180°/sec (r = -0.14, p = 0.037), and knee flexor strength at 60°/sec (r = -0.15, p = 0.021). After adjustment for potential confounders, the values of knee extensor strength at 60°/sec showed a trend toward a progressive reduction across IL-6 tertiles as IL-6 levels increased (p = 0.024). No significant association was found between IL-6 and other objectively measured physical performance. The findings were generally of smaller magnitude and less consistent than previously reported, which suggests that the associations are attenuated in those with both elevated inflammation and mobility limitations. These results have implications for planning and interpreting future intervention studies in older adults with low-grade inflammation and mobility limitations., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Maintaining physical mobility is important for preventing age-related comorbidities in older adults. Endurance and resistance training prevent mobility loss in aging, but exercise alone does not always achieve the expected improvements in physical and cardiopulmonary function. Recent preclinical evidence suggests that a reason for the variability in exercise training responses may be the age-related dysregulation of the nicotinamide adenine dinucleotide (NAD+) metabolome. NAD+ is an essential enzymatic cofactor in energetic and signaling pathways. Endogenous NAD+ pool is lower in several chronic and degenerative diseases (e.g., cardiovascular diseases, Alzheimer's and Parkinson's diseases, muscular dystrophies), and also in aging. Exercise requires a higher energy expenditure than a resting state, thus a state of NAD+ insufficiency with reduced energy metabolism, could result in an inadequate exercise response. Recently, the NAD+ precursor nicotinamide riboside (NR), a vitamin B3 derivate, showed an ability to improve NAD+ metabolome homeostasis, restoring energy metabolism and cellular function in various organs in animals. NR has also been tested in older humans and is considered safe, but the effects of NR supplementation alone on physical performance are unclear. The purpose of this review is to examine the preclinical and clinical evidence on the effect of NR supplementation strategies alone and in combination with physical activity on mobility and skeletal muscle and cardiovascular function., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Inc.)

Older adults are at high risk of developing cardiovascular disease (CVD). Pre-clinical studies indicate that resveratrol (RSV), a polyphenol commonly found in grapes and red wine, may help prevent development of CVD. Based on our previous reports where the 300 mg and 1000 mg doses appeared safe and improved psychomotor function in a dose-dependent manner, our hypothesis was that RSV would reduce biomarkers of CVD risk in overweight, but otherwise healthy older adults and that 1000 mg would lower CVD biomarkers >300 mg. This analysis was performed on samples from older participants (65 years and older) who were randomized to a 90 day RSV treatment with 300 mg (n = 10), 1000 mg (n = 9) or placebo (n = 10). We measured levels of CVD risk biomarkers i.e. oxidized low-density lipoprotein (oxLDL), soluble E-selectin-1 (sE-selectin), soluble Intercellular Adhesion Molecule-1 (sICAM-1), Soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1), total plasminogen activator inhibitor (tPAI-1). Statistical significance was set at p < 0.05. Both sVCAM-1 and tPAI increased significantly more in the 1000 mg vs. 300 mg and placebo groups. Other biomarkers (300 mg vs. 1000 mg vs. placebo: oxLDL, sEselectin-1 and sICAM-1) followed the same trend toward higher levels in the 1000 mg group compared to the 300 mg and placebo groups, without reaching statistical significance. This pilot project suggests that a higher dose of RSV may increase the levels of CVD risk biomarkers in overweight older adults. Given no change in the CVD risk biomarkers in response to a lower dose, future studies should test the effects of different doses of RSV to evaluate potential detrimental effects of higher doses on CVD biomarkers and measures of cardiovascular function in older adults at risk for CVD., Competing Interests: Declaration of competing interest None., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high-functioning (HF) and low-functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants. Finally, a negative correlation was determined between ZIP14 expression and circulating IL6 levels in LF older adults. None of assayed parameters differed between HF and LF participants. Our findings suggest that muscle iron homeostasis is altered in old age, which might contribute to loss of mtDNA stability. Muscle iron metabolism may therefore represent a target for interventions against muscle aging.

Background: Sepsis survivors often develop chronic critical illness (CCI) and demonstrate the persistent inflammation, immunosuppression, and catabolism syndrome predisposing them to long-term functional limitations and higher mortality. There is a need to identify biomarkers that can predict long-term worsening of physical function to be able to act early and prevent mobility loss. N-terminal pro-brain natriuretic peptide (NT-proBNP) is a well-accepted biomarker of cardiac overload, but it has also been shown to be associated with long-term physical function decline. We explored whether NT-proBNP blood levels in the acute phase of sepsis are associated with physical function and muscle strength impairment at 6 and 12 months after sepsis onset., Methods: This is a retrospective analysis conducted in 196 sepsis patients (aged 18-86 years old) as part of the University of Florida (UF) Sepsis and Critical Illness Research Center (SCIRC) who consented to participate in the 12-month follow-up study. NT-proBNP was measured at 24 h after sepsis onset. Patients were followed to determine physical function by short physical performance battery (SPPB) test score (scale 0 to12-higher score corresponds with better physical function) and upper limb muscle strength by hand grip strength test (kilograms) at 6 and 12 months. We used a multivariate linear regression model to test an association between NT-proBNP levels, SPPB, and hand grip strength scores. Missing follow-up data or absence due to death was accounted for by using inverse probability weighting based on concurrent health performance status scores. Statistical significance was set at p ≤ 0.05., Results: After adjusting for covariates (age, gender, race, Charlson comorbidity index, APACHE II score, and presence of CCI condition), higher levels of NT-proBNP at 24 h after sepsis onset were associated with lower SPPB scores at 12 months (p < 0.05) and lower hand grip strength at 6-month (p < 0.001) and 12-month follow-up (p < 0.05)., Conclusions: NT-proBNP levels during the acute phase of sepsis may be a useful indicator of higher risk of long-term impairments in physical function and muscle strength in sepsis survivors.

Objectives: This study sought to examine mortality, health-related quality of life, and physical function among sepsis survivors who developed chronic critical illness., Design: Single-institution, prospective, longitudinal, observational cohort study assessing 12-month outcomes., Setting: Two surgical/trauma ICUs at an academic tertiary medical and level 1 trauma center., Patients: Adult critically ill patients that survived 14 days or longer after sepsis onset., Interventions: None., Measurements and Main Results: Baseline patient characteristics and function, sepsis severity, and clinical outcomes of the index hospitalization were collected. Follow-up physical function (short physical performance battery; Zubrod; hand grip strength) and health-related quality of life (EuroQol-5D-3L, Short Form-36) were measured at 3, 6, and 12 months. Hospital-free days and mortality were determined at 12 months. We compared differences in long-term outcomes between subjects who developed chronic critical illness (≥ 14 ICU days with persistent organ dysfunction) versus those with rapid recovery. The cohort consisted of 173 sepsis patients; 63 (36%) developed chronic critical illness and 110 (64%) exhibited rapid recovery. Baseline physical function and health-related quality of life did not differ between groups. Those who developed chronic critical illness had significantly fewer hospital-free days (196 ± 148 vs 321 ± 65; p < 0.0001) and reduced survival at 12-months compared with rapid recovery subjects (54% vs 92%; p < 0.0001). At 3- and 6-month follow-up, chronic critical illness patients had significantly lower physical function (3 mo: short physical performance battery, Zubrod, and hand grip; 6 mo: short physical performance battery, Zubrod) and health-related quality of life (3- and 6-mo: EuroQol-5D-3L) compared with patients who rapidly recovered. By 12-month follow-up, chronic critical illness patients had significantly lower physical function and health-related quality of life on all measures., Conclusions: Surgical patients who develop chronic critical illness after sepsis exhibit high healthcare resource utilization and ultimately suffer dismal long-term clinical, functional, and health-related quality of life outcomes. Further understanding of the mechanisms driving the development and persistence of chronic critical illness will be necessary to improve long-term outcomes after sepsis.

Exercise is widely recognized as a critical component of a healthy lifestyle by multiple scientific and regulatory bodies. Yet only 35% of adults in the United States even report engaging in regular physical activity. In response to this challenge, the Exercise is Medicine (EIM) initiative encourages clinicians in all settings to regularly assess and counsel patients on physical activity in an attempt to reduce levels of inactivity. The purpose of this article is to highlight key challenges to the implementation of the EIM initiative to promote physical activity and to identify potential opportunities to overcome these challenges. EIM is a global health initiative that endorses "exercise" to be a "vital sign" in all clinical settings. Specifically to assess and compare the patient's physical activity level to national guidelines for physical activity and then promote discussions or referrals based on results. Since its 2007 launch, advocates of the EIM initiative have increased global awareness to promote the EIM mission of integrating and implementing physical activity into healthcare systems, local communities, and individuals' daily lives. Physical activity is fundamental to the overall health of all people across all geographic locations and throughout the lifespan. Promoting physical activity as a healthy lifestyle change has specific challenges but necessary to decrease health disparities related to inactivity., Competing Interests: Disclosure of Potential Conflicts of Interest The above listed grants supported protected time for the authors to complete the work. The authors do not have any conflicts of interest to disclose. The views of this manuscript do not constitute any official endorsement of the American College of Sports Medicine.

Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Advancing age is a major risk factor for developing cardiovascular disease because of the lifelong exposure to cardiovascular risk factors and specific alterations affecting the heart and the vasculature during ageing. Indeed, the ageing heart is characterized by structural and functional changes that are caused by alterations in fundamental cardiomyocyte functions. In particular, the myocardium is heavily dependent on mitochondrial oxidative metabolism and is especially susceptible to mitochondrial dysfunction. Indeed, primary alterations in mitochondrial function, which are subsequently amplified by defective quality control mechanisms, are considered to be major contributing factors to cardiac senescence. In this Review, we discuss the mechanisms linking defective mitochondrial quality control mechanisms (that is, proteostasis, biogenesis, dynamics, and autophagy) to organelle dysfunction in the context of cardiac ageing. We also illustrate relevant molecular pathways that might be exploited for the prevention and treatment of age-related heart dysfunction.

Growing evidence suggests chronic low-grade inflammation (LGI) as a possible mechanism underlying the aging process. Some biological and pharmaceutical compounds may reduce systemic inflammation and potentially avert functional decline occurring with aging. The aim of the present meta-analysis was to examine the association of pre-selected interventions on two established biomarkers of inflammation, interleukin-6 (IL-6), and C-reactive protein (CRP) in middle-age and older adults with chronic LGI. We reviewed the literature on potential anti-inflammatory compounds, selecting them based on safety, tolerability, acceptability, innovation, affordability, and evidence from randomized controlled trials. Six compounds met all five inclusion criteria for our systematic review and meta-analysis: angiotensin II receptor blockers (ARBs), metformin, omega-3, probiotics, resveratrol and vitamin D. We searched in MEDLINE, PubMed and EMBASE database until January 2017. A total of 49 articles fulfilled the selection criteria. Effect size of each study and pooled effect size for each compound were measured by the standardized mean difference. I 2 was computed to measure heterogeneity of effects across studies. The following compounds showed a significant small to large effect in reducing IL-6 levels: probiotics (-0.68 pg/ml), ARBs (-0.37 pg/ml) and omega-3 (-0.19 pg/ml). For CRP, a significant small to medium effect was observed with probiotics (-0.43 mg/L), ARBs (-0.2 mg/L), omega-3 (-0.17 mg/L) and metformin (-0.16 mg/L). Resveratrol and vitamin D were not associated with any significant reductions in either biomarker. These results suggest that nutritional and pharmaceutical compounds can significantly reduce established biomarkers of systemic inflammation in middle-age and older adults. The findings should be interpreted with caution, however, due to the evidence of heterogeneity across the studies., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The purpose of this trial was to study the effects of chronic resveratrol use on cognitive function in humans., Design: The authors conducted a double-blind, Phase IIa randomized, placebo-controlled trial to obtain preliminary estimates of the effects of resveratrol supplementation on cognitive function over a 90-day period in older adults., Location: University of Florida in Gainesville, FL., Subjects: Sedentary, overweight older adults (N = 32; age range: 65-93 years, M age = 73.34 years, SD age = 7.02 years)., Intervention: Participants were randomized to one of three treatment groups (placebo, 300 mg/day resveratrol, 1000 mg/day resveratrol) for 90 days., Outcome Measures: Cognitive function was assessed before and after treatment using a well-characterized test battery: Trail Making, Digits Forward and Backward, Erikson-Flanker, Controlled Oral Word Association, Hopkins Verbal Learning Test-Revised, and Task Switching., Results: Psychomotor speed improved on the Trail Making Test part A in participants taking 1000 mg/day of resveratrol compared with participants in both the 300 mg/day condition and the placebo condition (p = 0.02)., Conclusion: This pilot study suggests that 90 days of resveratrol supplementation at a dose of 1000/mg per day selectively improves psychomotor speed but does not significantly affect other domains of cognitive function in older adults. These findings provide modest support to further study the effects of resveratrol on cognitive function in older adults.

Fermented Papaya Preparation (FPP®) has shown antioxidative and anti-inflammatory effects in preclinical and clinical aging studies. However, clinical trials are needed to fully evaluate the safety of FPP® in moderate-functioning, generally healthy older adults. In this randomized (9g/day of FPP® or placebo), crossover design study, we enrolled 30 older moderate-functioning older adults (70-100 years old). The participants completed both a treatment and a placebo condition. After eight (8) weeks on each of these regimens (with a 4-week wash-out period in between), participants had their venous blood drawn for assessment of blood chemistries, metabolic outcomes and inflammatory biomarkers. Participants were asked to report any adverse events during the course of the study and complete post-treatment outcome assessments for anthropometric and metabolic outcomes. The major finding related to safety was that there were no adverse changes in blood chemistries and few adverse events in the FPP® condition, which did not differ from placebo (p>0.05). There were no serious adverse effects in either condition. Twenty-nine (29) participants (mean age 78.2±5.3 yrs) completed the study with 94% adherence to the dosing regimen. There were no significant effects of FPP® on anthropometric and metabolic outcomes. In addition, no effects on markers of inflammation were observed. Our trial demonstrates FPP® supplementation is safe and feasible in adults ages 70 years and older. Based on these findings and the positive effects FPP has demonstrated in previous trials, future trials should examine the effects of FPP® in older adults with impaired health status and/or older adults who may have insufficient anti-oxidant protection due to their genetic background., Competing Interests: The authors declare no conflict of interest.

Objectives: To examine associations between objectively measured physical activity (PA) and incidence of major mobility disability (MMD) and persistent MMD (PMMD) in older adults in the Lifestyle Interventions and Independence for Elders (LIFE) Study., Design: Prospective cohort of individuals aged 65 and older undergoing structured PA intervention or health education., Setting: The LIFE Study was a multicenter (eight sites) randomized controlled trial designed to compare the efficacy of a long-term structured PA intervention with that of a health education (HE) program in reducing the incidence of MMD in mobility-limited older adults., Participants: LIFE Study participants (n = 1,590) had a mean age±standard deviation of 78.9 ± 5.2, low levels of PA, and measured mobility-relevant functional impairment at baseline., Measurements: Activity data were collected using hip-worn 7-day accelerometers at baseline and 6, 12, and 24 months after randomization to test for associations with incident MMD and PMMD (≥2 consecutive instances of MMD)., Results: At baseline, every 30 minutes spent being sedentary (<100 accelerometry counts per minute) was associated with higher rate of subsequent MMD (10%) and PMMD (11%) events. Every 500 steps taken was associated with lower rate of MMD (15%) and PMMD (18%). Similar associations were observed when fitting accelerometry-based PA as a time-dependent variable., Conclusion: Accelerometry-based PA levels were strongly associated with MMD and PMMD events in older adults with limited mobility. These results support the importance of daily PA and lower amounts of sedentary time levels in this population and suggest that accelerometry may be a useful tool for assessing risk of mobility disability., (© 2017, Copyright the Authors Journal compilation © 2017, The American Geriatrics Society.)

Skeletal muscle mitochondrial function declines with age and is a key factor in the maintenance of physical function among older adults. Research studies from animals and humans have consistently demonstrated that exercise improves skeletal muscle mitochondrial function in early and middle adulthood. However, mitochondrial adaptations to both acute and chronic exercise are attenuated in late life. Thus, there is an important need to identify adjuvant therapies capable of augmenting mitochondrial adaptations to exercise (e.g. improved mitochondrial respiration, muscle mitochondria biogenesis) among older adults. This study is investigating the potential of resveratrol supplementation for this purpose. The objective of this randomized, double-masked pilot trial is to evaluate the efficacy of resveratrol supplementation combined with a comprehensive supervised exercise program exercise for improving physical function among older adults. Moderately functioning, sedentary participants aged ≥60 years will perform 24 sessions (2 day/wk for 12 weeks) of center-based walking and resistance training and are randomly assigned to receive either (1) 500 mg/day resveratrol (2) 1000 mg/day resveratrol or (3) placebo. Study dependent outcomes include changes in 1) knee extensor strength, 2) objective measures of physical function (e.g. 4m walk test, Short Physical Performance Battery), 3) subjective measures of physical function assessed by Late Life Function and Disability Instrument, and 4) skeletal muscle mitochondrial function. This study will provide novel information regarding the therapeutic potential of resveratrol supplementation combined with exercise while also informing about the long-term clinical viability of the intervention by evaluating participant safety and willingness to engage in the intervention.

Purpose: It is still equivocal whether oxygen uptake recovery kinetics are limited by oxygen delivery and can be improved by supplementary oxygen. The present study aimed to investigate whether measurements of muscle and pulmonary oxygen uptake kinetics can be used to assess oxygen delivery limitations in healthy subjects., Methods: Sixteen healthy young adults performed three sub-maximal exercise tests (6 min at 40% W max ) under hypoxic (14%O 2 ), normoxic (21%O 2 ) and hyperoxic (35%O 2 ) conditions on separate days in randomized order. Both Pulmonary VO 2 and near infra red spectroscopy (NIRS) based Tissue Saturation Index (TSI) offset kinetics were calculated using mono-exponential curve fitting models., Results: Time constant τ of VO 2 offset kinetics under hypoxic (44.9 ± 7.3s) conditions were significantly larger than τ of the offset kinetics under normoxia (37.9 ± 8.2s, p = 0.02) and hyperoxia (37±6s, p = 0.04). TSI mean response time (MRT) of the offset kinetics under hypoxic conditions (25.5 ± 13s) was significantly slower than under normoxic (15 ± 7.7, p = 0.007) and hyperoxic (13 ± 7.3, p = 0.008) conditions., Conclusion: The present study shows that there was no improvement in the oxygen uptake and muscle oxygenation recovery kinetics in healthy subjects under hyperoxic conditions.Slower TSI and VO 2 recovery kinetics under hypoxic conditions indicate that both NIRS and spiro-ergometry are appropriate non-invasive measurement tools to assess the physiological response of a healthy individual to hypoxic exercise.

Mankowski, RT, Michael, S, Rozenberg, R, Stokla, S, Stam, HJ, and Praet, SFE. Heart-rate variability threshold as an alternative for spiro-ergometry testing: a validation study. J Strength Cond Res 31(2): 474-479, 2017-Although spiro-ergometry is the established "gold standard" for determination of the second ventilatory threshold (VT2), it is a costly and rather time-consuming method. Previous studies suggest that assessing the second anaerobic threshold (AT2) on the basis of heart rate variability (HRV) during exercise may be a more cost-effective and noninvasive manner. However, appropriate validation studies, are still lacking. Eleven healthy, moderately trained subjects underwent 3 incremental exercise tests. Ventilation, oxygen uptake (V[Combining Dot Above]O2), CO2 production (V[Combining Dot Above]CO2), and HRV were measured continuously. Exercise testing was performed in 3 oxygen (FiO2) conditions of inspired air (14, 21, and 35% of oxygen). Participants and assessors were blinded to the FiO2 conditions. Two research teams assessed VT2s and HRVT2s independently from each other. Mean workloads corresponding to VT2 and HRVT2 in hypoxia were, respectively, 19 ± 17% (p = 0.01) and 15 ± 15% (p = 0.1) lower in comparison with hyperoxic conditions. Bland-Altman analysis showed low estimation bias (2.2%) and acceptably precise 95% limits of agreement for workload -15.7% to 20.1% for all FiO2 conditions. Bias was the lowest under normoxic conditions (1.1%) in comparison with hypoxia (3.7%) and hyperoxia (4.7%). Heart rate variability-based AT2 assessment had a most acceptable agreement with VT2 under normoxic conditions. This simple HRVT2 assessment may have potential applications for exercise monitoring in commercial fitness settings.

In this report we describe a female Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) patient who suffered from severe exercise intolerance. At age 34, the patient became pregnant for the first time. After an uneventful first 32 weeks of pregnancy she developed sinus tachycardia (resting heart rate 120-134 bpm) and lactate and creatinine kinase levels increased (3.3 mmol/L and 264 U/L, respectively). Increasing MCT supplementation (dose and frequency of administration) lowered heart rate and improved biochemical parameters. At 34 weeks the heart rate rose again and it was decided to deliver the child by caesarean section. Postpartum both mother and child did well.Prior to pregnancy, she performed exercise tests with different doses of medium chain triglycerides (MCTs) to establish a safe and effective exercise program (baseline test, second test with 10 g MCTs and third test with 20 g of MCTs). In the MCT supplemented tests the maximal power output was 23% (second test) and 26% (third test) higher, while cardiac output at maximal power output was the same in all three tests (~15.8 L/min).In conclusion, this is the first report of pregnancy in an LCHADD patient, with favourable outcome for both mother and child. Moreover, in the same patient, MCT supplementation improved cardiac performance and metabolic parameters during high intensity exercise. Using impedance cardiography, we got a clear indication that this benefit was due to improved muscle energy generation at high intensity exercise, since at the same cardiac output a higher power output could be generated.