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Abstract Background SARS-CoV-2 infection has raised concerns about long-term health repercussions. Exercise ventilatory inefficiency (EVin) has emerged as a notable long-term sequela, potentially impacting respiratory and cardiovascular health. This study aims to assess the long-term presence of EVin after 34 months and its association with cardiorespiratory health in post-COVID patients. Methods In a longitudinal study on 32 selected post-COVID subjects, we performed two cardiopulmonary exercise tests (CPETs) at 6 months (T0) and 34 months (T1) after hospital discharge. The study sought to explore the long-term persistence of EVin and its correlation with respiratory and cardiovascular responses during exercise. Measurements included also V̇O2peak, end-tidal pressure of CO2 (PETCO2) levels, oxygen uptake efficiency slope (OUES) and other cardiorespiratory parameters, with statistical significance set at p

Abstract The downward slope during the near‐infrared spectroscopy (NIRS)‐vascular occlusion test (NIRS‐VOT) is purported as a simplified estimate of metabolism. Whether or not the NIRS‐VOT exhibits sex‐ or limb‐specificity or may be acutely altered remains to be elucidated. Thus, we investigated if there is limb‐ or sex specificity in tissue desaturation rates (DeO2) during a NIRS‐VOT, and if acute dietary capsaicin may alter this estimate of muscle metabolism. Young healthy men (n = 25, 21 ± 4 years) and women (n = 20, 20 ± 1 years) ingested either placebo or capsaicin, in a counterbalanced, single‐blind, crossover design after which a simplified NIRS‐VOT was conducted to determine the DeO2 (%/s), as an estimate of oxidative muscle metabolism, in both the forearm (flexors) and thigh (vastus lateralis). There was a significant limb effect with the quadriceps having a greater DeO2 than the forearm (−2.31 ± 1.34 vs. −1.78 ± 1.22%/s, p = 0.007, ηp2 = 0.19). There was a significant effect of sex on DeO2 (p = 0.005, ηp2 = 0.203) with men exhibiting a lesser DeO2 than women (−1.73 ± 1.03 vs. −2.36 ± 1.32%/s, respectively). This manifested in significant interactions of limb*capsaicin (p = 0.001, ηp2 = 0.26) as well as limb*capsaicin*sex on DeO2 (p = 0.013, ηp2 = 0.16) being observed. Capsaicin does not clearly alter O2‐dependent muscle metabolism, but there was apparent limb and sex specificity, interacting with capsaicin in this NIRS‐derived assessment.

Objective Upper-limb exercise is recommended for patients with COPD, albeit there are limited data concerning the optimal modality to implement. We compared interval (INT-EX) to continuous (CONT-EX) upper-limb exercise in terms of exercise tolerance, ventilatory and metabolic responses when both conditions were sustained at an equivalent work rate. Methods 26 stable COPD patients undertook three upper-limb exercise sessions to initially establish peak work rate (PWR) via an incremental exercise test and subsequently two equivalent work rate tests to the limit tolerance in balanced order: 1) INT-EX consisting of 30-s work at 100% PWR interspersed with 30-s work at 40% of PWR; and 2) CONT-EX at 70% PWR. Results 20 patients (76.9%) had longer tolerance during INT-EX, while six out of 26 (23.1%) exhibited longer tolerance during CONT-EX. The average endurance time was 434.1±184.7 and 315.7±128.7 s for INT-EX and CONT-EX, respectively. During INT-EX at isotime (i.e. when work completed was the same between INT-EX and CONT-EX), the majority of patients manifested lower oxygen uptake, minute ventilation, pulmonary hyperinflation, heart rate, symptoms and higher CO2 blood concentration. Patients with longer INT-EX had a lower comorbidity score (Cumulative Illness Rating Scale: 1.58±0.30 versus 1.88±0.29, p=0.0395) and better-preserved lung function (forced vital capacity 84.7±15.31% versus 67.67±20.56%, p=0.0367; forced expiratory volume in 1 s 57.15±14.59 versus 44.67±12.99% predicted, p=0.0725) compared to patients with longer CONT-EX. Conclusion INT-EX is more sustainable than CONT-EX for the majority of COPD patients with moderate obstruction, leading to lower dynamic hyperinflation and symptoms at isotime. Further studies need to define the benefits of its application during pulmonary rehabilitation.

Objective Protein–energy malnutrition and the subsequent muscle wasting (sarcopenia) are common ageing complications. It is knowing to be also associated with dementia. Our programme will test the cytoprotective functions of vitamin E combined with the cortisol-lowering effect of chocolate polyphenols (PP), in combination with muscle anabolic effect of adequate dietary protein intake and physical exercise to prevent the age-dependent decline of muscle mass and its key underpinning mechanisms including mitochondrial function, and nutrient metabolism in muscle in the elderly.Methods and analysis In 2020, a 6-month double-blind randomised controlled trial in 75 predementia older people was launched to prevent muscle mass loss, in respond to the ‘Joint Programming Initiative A healthy diet for a healthy life’. In the run-in phase, participants will be stabilised on a protein-rich diet (0.9–1.0 g protein/kg ideal body weight/day) and physical exercise programme (high-intensity interval training specifically developed for these subjects). Subsequently, they will be randomised into three groups (1:1:1). The study arms will have a similar isocaloric diet and follow a similar physical exercise programme. Control group (n=25) will maintain the baseline diet; intervention groups will consume either 30 g/day of dark chocolate containing 500 mg total PP (corresponding to 60 mg epicatechin) and 100 mg vitamin E (as RRR-alpha-tocopherol) (n=25); or the high polyphenol chocolate without additional vitamin E (n=25). Muscle mass will be the primary endpoint. Other outcomes are neurocognitive status and previously identified biomolecular indices of frailty in predementia patients. Muscle biopsies will be collected to assess myocyte contraction and mitochondrial metabolism. Blood and plasma samples will be analysed for laboratory endpoints including nutrition metabolism and omics.Ethics and dissemination All the ethical and regulatory approvals have been obtained by the ethical committees of the Azienda Ospedaliera Universitaria Integrata of Verona with respect to scientific content and compliance with applicable research and human subjects’ regulation. Given the broader interest of the society toward undernutrition in the elderly, we identify four main target audiences for our research activity: national and local health systems, both internal and external to the project; targeted population (the elderly); general public; and academia. These activities include scientific workshops, public health awareness campaigns, project dedicated website and publication is scientific peer-review journals.Trial registration number NCT05343611.

Abstract The purpose of this review is to describe the present evidence for exercise and nutritional interventions as potential contributors in the treatment of sarcopenia and frailty (i.e. muscle mass and physical function decline) and the risk of cardiorenal metabolic comorbidity in people with heart failure (HF). Evidence primarily from cross‐sectional studies suggests that the prevalence of sarcopenia in people with HF is 37% for men and 33% for women, which contributes to cardiac cachexia, frailty, lower quality of life, and increased mortality rate. We explored the impact of resistance and aerobic exercise, and nutrition on measures of sarcopenia and frailty, and quality of life following the assessment of 35 systematic reviews and meta‐analyses. The majority of clinical trials have focused on resistance, aerobic, and concurrent exercise to counteract the progressive loss of muscle mass and strength in people with HF, while promising effects have also been shown via utilization of vitamin D and iron supplementation by reducing tumour necrosis factor‐alpha (TNF‐a), c‐reactive protein (CRP), and interleukin‐6 (IL‐6) levels. Experimental studies combining the concomitant effect of exercise and nutrition on measures of sarcopenia and frailty in people with HF are scarce. There is a pressing need for further research and well‐designed clinical trials incorporating the anabolic and anti‐catabolic effects of concurrent exercise and nutrition strategies in people with HF.

Fatigue is one of the most disabling symptoms of multiple sclerosis (MS); it influences patients’ quality of life. The etiology of fatigue is complex, and its pathogenesis is still unclear and debated. The objective of this review was to describe potential brain structural and functional dysfunctions underlying fatigue symptoms in patients with MS. To reach this purpose, a systematic review was conducted of published studies comparing functional brain activation and structural brain in MS patients with and without fatigue. Electronic databases were searched until 24 February 2021. The structural and functional outcomes were extracted from eligible studies and tabulated. Fifty studies were included: 32 reported structural brain differences between patients with and without fatigue; 14 studies described functional alterations in patients with fatigue compared to patients without it; and four studies showed structural and functional brain alterations in patients. The results revealed structural and functional abnormalities that could correlate to the symptom of fatigue in patients with MS. Several studies reported the differences between patients with fatigue and patients without fatigue in terms of conventional magnetic resonance imaging (MRI) outcomes and brain atrophy, specifically in the thalamus. Functional studies showed abnormal activation in the thalamus and in some regions of the sensorimotor network in patients with fatigue compared to patients without it. Patients with fatigue present more structural and functional alterations compared to patients without fatigue. Specifically, abnormal activation and atrophy of the thalamus and some regions of the sensorimotor network seem linked to fatigue.

The current randomized controlled study investigated whether or not the inclusion of the eccentric phase in resistance training favors the contralateral strength gains after different unilateral protocols, and whether such gains are retained after detraining. Sixty healthy women were randomly assigned to a unilateral concentric-only (CONC), eccentric-only (ECC), concentric–eccentric (TRAD) volume-equated knee extension training or control group (CON). The participants trained 2 days/week for 8 weeks and then did not train for further 8 weeks. Knee extensors isokinetic concentric, eccentric, and isometric peak torque and vastus lateralis muscle thickness were assessed in the contralateral limb at baseline, post-training, and post-detraining. At post-training, concentric peak torque increased in CONC [+9.2%, 95%CI (+6.2/+12.3), p 0.05). Muscle thickness did not change in any group (p > 0.05). At post-detraining, all groups preserved the contralateral strength gains observed at post-training (p

Absent or reduced physical activity and spontaneous movement over days, weeks, or even years may lead to problems in almost every major organ/system in the human body. In this study, we investigated whether the dysregulation and alteration of plasma protein inflammatory profiling can stratify chronic bedridden conditions observed in 22 elderly chronic bedridden (CBR) individuals with respect to 11 age-matched active (OLD) controls. By using a combination of immune-assay multiplex techniques, a complex of 27 inflammatory mediators was assessed in the plasma collected from the two groups. A specific plasma protein signature is indeed able to distinguish IPO individuals from age-matched OLD controls; while significantly (p < 0.001) higher protein levels of IL-2, IL-7, and IL-12p70 were measured in the plasma of CBR with respect to OLD individuals, significantly (p < 0.01) higher levels of seven inflammatory mediators, including IL-9, PDGF-b, CCL4 (MIP-1b), CCL5 (RANTES), IL-1Ra, CXCL10 (IP10), and CCL2 (MCP-1), were identified in OLD individuals with respect to CBR individuals. These data suggest that the chronic absence of physical activity may contribute to the dysregulation of a complex molecular pattern occurring with ageing and that specific plasma protein signatures may represent potential biomarkers as well as new potential therapeutic targets for new treatments aimed at improving health expectancy.

Background: Stroke is a leading cause of disability. Nonetheless, the care pathway for stroke rehabilitation takes partially into account the needs of chronic patients. This is due in part to the lack of evidence about the mechanisms of recovery after stroke, together with the poor knowledge of related and influencing factors. Here we report on the study protocol “Rehabilitation and Biomarkers of Stroke Recovery,” which consists of 7 work-packages and mainly aim to investigate the effects of long-term neurorehabilitation on stroke patients and to define a related profile of (clinical-biological, imaging, neurophysiological, and genetic-molecular) biomarkers of long-term recovery after stroke. The work-package 1 will represent the main part of this protocol and aims to compare the long-term effects of intensive self-rehabilitation vs. usual (rehabilitation) care for stroke.Methods: We planned to include a total of 134 adult subacute stroke patients (no more than 3 months since onset) suffering from multidomain disability as a consequence of first-ever unilateral ischemic stroke. Eligible participants will be randomly assigned to one of the following groups: intensive self-rehabilitation (based on the principles of “Guided Self-Rehabilitation Contract”) vs. usual care (routine practice). Treatment will last 1 year, and patients will be evaluated every 3 months according to their clinical presentation. The following outcomes will be considered in the main work-package: Fugl-Meyer assessment, Cognitive Oxford Screen Barthel Index, structural and functional neuroimaging, cortical excitability, and motor and somatosensory evoked potentials.Discussion: This trial will deal with the effects of an intensive self-management rehabilitation protocol and a related set of biomarkers. It will also investigate the role of training intensity on long-term recovery after stroke. In addition, it will define a set of biomarkers related to post-stroke recovery and neurorehabilitation outcome in order to detect patients with greater potential and define long-term individualized rehabilitation programs.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT04323501.

To date there is no anthropometric equation specific to athletes with unilateral lower limb amputation to estimate the percentage of fat mass (%FM). This study investigated the accuracy of a set of anthropometric equations validated on able-bodied populations to predict the %FM assessed by-means of dual-energy x-ray absorptiometry (DXA) in athletes with unilateral lower limb amputation. Furthermore, a predictive anthropometric equation specific to athletes with unilateral lower limb amputation was developed from skinfold thickness measurements using DXA as the reference method for the estimation of the %FM. Twenty-nine white male athletes with unilateral lower limb amputation underwent a DXA scan and an anthropometric assessment on the same day. The %FM, calculated through several existing anthropometric equations validated upon able-bodied populations, was compared with the DXA-measured %FM (%FM_DXA). Accuracy and agreement between the two methods was computed with two-tailed paired-sample t-test, concordance correlation coefficient, reduced major axis regression and Bland-Altman analysis. A stepwise multiple regression analysis with the %FM_DXA as the dependent variable and age and nine skinfold thicknesses as potential predictors was carried out and validated using a repeated 10-fold cross-validation. A linear regression analysis with the sum of nine skinfolds as the independent variable was also carried out and validated using a repeated 10-fold cross-validation. The results showed that the anthropometric equations validated on able-bodied populations are inaccurate in the estimation of %FM_DXA with an average bias ranging from 0.51 to −13.70%. Proportional bias was also found revealing that most of the anthropometric equations considered, tended to underestimate/overestimate the %FM_DXA as body fat increased. Regression analysis produced two statistically significant models (P < 0.001 for both) which were able to predict more than 93% of total variance of %FM_DXA from the values of four skinfold measurements (i.e., thigh, abdominal, subscapular and axillary skinfold measurements) or from the sum of 9 skinfolds. Repeated cross-validation analysis highlighted a good predictive performance of the proposed equations. The predictive equations proposed in this study represent a useful tool for clinicians, nutritionists, and physical conditioners to evaluate the physical and nutritional status of athletes with unilateral lower limb amputation directly in the field.

Capsaicin (CAP) activates the transient receptor potential vanilloid 1 (TRPV1) channel on sensory neurons, improving ATP production, vascular function, fatigue resistance, and thus exercise performance. However, the underlying mechanisms of CAP-induced ergogenic effects and fatigue-resistance, remain elusive. To evaluate the potential anti-fatigue effects of CAP, 10 young healthy males performed constant-load cycling exercise time to exhaustion (TTE) trials (85% maximal work rate) after ingestion of placebo (PL; fiber) or CAP capsules in a blinded, counterbalanced, crossover design, while cardiorespiratory responses were monitored. Fatigue was assessed with the interpolated twitch technique, pre-post exercise, during isometric maximal voluntary contractions (MVC). No significant differences (p > 0.05) were detected in cardiorespiratory responses and self-reported fatigue (RPE scale) during the time trial or in TTE (375 ± 26 and 327 ± 36 s, respectively). CAP attenuated the reduction in potentiated twitch (PL: −52 ± 6 vs. CAP: −42 ± 11%, p = 0.037), and tended to attenuate the decline in maximal relaxation rate (PL: −47 ± 33 vs. CAP: −29 ± 68%, p = 0.057), but not maximal rate of force development, MVC, or voluntary muscle activation. Thus, CAP might attenuate neuromuscular fatigue through alterations in afferent signaling or neuromuscular relaxation kinetics, perhaps mediated via the sarco-endoplasmic reticulum Ca2+ ATPase (SERCA) pumps, thereby increasing the rate of Ca2+ reuptake and relaxation.

The evidence demonstrating the benefits of exercise is indisputable for healthy subjects, and more recently, it is growing for Parkinson's disease (PD) patients. Due to its easy access, low cost, social facilitation and, above all, the symptomatic effect, clinical exercise may have a profound impact on PD management. Especially considering that in recent decades there have been no major advances from the pharmacological point of view. Despite this, clinical exercise use it stills limited by the existent flaws in the available evidence supporting its use and guiding its prescription as a PD therapeutic intervention. We believe that a approach from the most relevant scientific and clinical fields is crucial to establish the use of clinical exercise in PD patients' routine care. Therefore, in this viewpoint, we aim to highlight the importance of clinical exercise as a therapeutic intervention in PD, and particularly of the benefits of applying sports science principles to potentiate the use of clinical exercise as a therapeutic intervention in PD management.

We evaluated vascular dysfunction with the single passive leg movement test (sPLM) in 22 frail elderly patients at 84 + 31 days after hospitalization for COVID-19 pneumonia, compared to 22 age-, sex- and comorbidity-matched controls (CTRL). At rest, all COVID-19 patients were in stable clinical condition without severe comorbidities. Patients (aged 72 ± 6 years, 73% male) had moderate disability (Barthel index score 77 ± 26), hypoxemia and normocapnia at arterial blood gas analysis and mild pulmonary restriction at spirometry. Values of circulating markers of inflammation (C-reactive protein: CRP; erythrocyte sedimentation rate: ESR) and coagulation (D-dimer) were: 27.13 ± 37.52 mg/dL, 64.24 ± 32.37 mm/1 h and 1043 ± 729 ng/mL, respectively. At rest, femoral artery diameter was similar in COVID-19 and CTRL (p = 0.16). On the contrary, COVID-19 infection deeply impacted blood velocity (p = 0.001) and femoral blood flow (p < 0.0001). After sPLM, peak femoral blood flow was dramatically reduced in COVID-19 compared to CTRL (p = 0.001), as was blood flow ∆peak (p = 0.05) and the area under the curve (p < 0.0001). This altered vascular responsiveness could be one of the unknown components of long COVID-19 syndrome leading to fatigue, changes in muscle metabolism and fibers’ composition, exercise intolerance and increased cardiovascular risk. Impact of specific treatments, such as exercise training, dietary supplements or drugs, should be evaluated.

Vascular endothelial function is a strong marker of cardiovascular health and it refers to the ability of the body to maintain the homeostasis of vascular tone. The endothelial cells react to mechanical and chemical stimuli modulating the smooth muscle cells relaxation. The extent of the induced vasodilation depends on the magnitude of the stimulus. During exercise, the peripheral circulation is mostly controlled by the endothelial cells response that increases the peripheral blood flow in body districts involved but also not involved with exercise. However, whether vascular adaptations occur also in the brachial artery as a result of isolated leg extension muscles (KE) training is still an open question. Repetitive changes in blood flow occurring during exercise may act as vascular training for vessels supplying the active muscle bed as well as for the vessels of body districts not directly involved with exercise. This study sought to evaluate whether small muscle mass (KE) training would induce improvements in endothelial function not only in the vasculature of the lower limb (measured at the femoral artery level in the limb directly involved with training), but also in the upper limb (measured at the brachial artery level in the limb not directly involved with training) as an effect of repetitive increments in the peripheral blood flow during training sessions. Ten young healthy participants (five females, and five males; age: 23 ± 3 years; stature: 1.70 ± 0.11 m; body mass: 66 ± 11 kg; BMI: 23 ± 1 kg ⋅ m-2) underwent an 8-week KE training study. Maximum work rate (MWR), vascular function and peripheral blood flow were assessed pre- and post-KE training by KE ergometer, flow mediated dilatation (FMD) in the brachial artery (non-trained limb), and by passive limb movement (PLM) in femoral artery (trained limb), respectively. After 8 weeks of KE training, MWR and PLM increased by 44% (p = 0.015) and 153% (p = 0.003), respectively. Despite acute increase in brachial artery blood flow during exercise occurred (+25%; p < 0.001), endothelial function did not change after training. Eight weeks of KE training improved endothelial cells response only in the lower limb (measured at the femoral artery level) directly involved with training, likely without affecting the endothelial response of the upper limb (measured at the brachial artery level) not involved with training.

Mitochondrial encephalomyopathy, lactic acidosis, and recurrent stroke-like episodes syndrome (MELAS) is a rare degenerative disease. Recent studies have shown that resistant training (RT) can ameliorate muscular force in mitochondrial diseases. However, the effects of RT in MELAS are unknown. The aim of this case report was to investigate the effects of RT on skeletal muscle and mitochondrial function in a 21-years old patient with MELAS. RT included 12 weeks of RT at 85% of 1 repetition maximum. Body composition (DXA), in vivo mitochondrial respiration capacity (mVO2) utilizing Near-infrared spectroscopy on the right plantar-flexor muscles, maximal voluntary torque (MVC), electrically evoked resting twitch (EET) and maximal voluntary activation (VMA) of the right leg extensors (LE) muscles were measured with the interpolated twitch technique. The participant with MELAS exhibited a marked increase in body mass (1.4 kg) and thigh muscle mass (0.3 kg). After the training period MVC (+5.5 Nm), EET (+2.1 N⋅m) and VMA (+13.1%) were ameliorated. Data of mVO2 revealed negligible changes in the end-exercise mVO2 (0.02 mM min-1), Δ mVO2 (0.09 mM min-1), while there was a marked amelioration in the kinetics of mVO2 (τ mVO2; Δ70.2 s). This is the first report of RT-induced ameliorations on skeletal muscle and mitochondrial function in MELAS. This case study suggests a preserved plasticity in the skeletal muscle of a patient with MELAS. RT appears to be an effective method to increase skeletal muscle function, and this effect is mediated by both neuromuscular and mitochondrial adaptations.

The oldest-old, in the ninth and tenth decades of their life, represent a population characterized by neuromuscular impairment, which often implies a loss of mobility and independence. As recently documented by us and others, muscle atrophy and weakness are accompanied by an unexpected preservation of the size and contractile function of skeletal muscle fibers. This suggests that, while most fibers are likely lost with their respective motoneurons, the surviving fibers are well preserved. Here, we investigated the mechanisms behind this fiber preservation and the relevance of physical activity, by comparing a group of 6 young healthy controls (YG: 22–28 years) with two groups of oldest-old (81–96 years), one able to walk (OW: n = 6, average 86 years) and one confined to a wheelchair (ONW n = 9, average 88 years). We confirmed previous results of fiber preservation and, additionally, observed a shift in fiber type, toward slow predominance in OW and fast predominance in ONW. Myonuclear density was increased in muscles of ONW, compared to YG and OW, potentially indicative of an ongoing atrophy process. We analyzed, by RT-qPCR, the expression of genes relevant for fiber size and type regulation in a biopsy sample from the vastus lateralis. In all oldest-old both myostatin and IGF-1 expression were attenuated compared to YG, however, in ONW two specific IGF-1 isoforms, IGF-1EA and MGF, demonstrated a further significant decrease compared to OW. Surprisingly, atrogenes (MURF1 and atrogin) expression was also significantly reduced compared to YG and this was accompanied by a close to statistically significantly attenuated marker of autophagy, LC3. Among the determinants of the metabolic fiber type, PGC1α was significantly reduced in both OW and ONW compared to YG, while AMPK was down-regulated only in ONW. We conclude that, in contrast to the shift of the balance in favor of pro-atrophy factors found by other studies in older adults (decreased IGF-1, increase of myostatin, increase of atrogenes), in the oldest-old the pro-atrophy factors also appear to be down-regulated, allowing a partial recovery of the proteostasis balance. Furthermore, the impact of muscle activity, as a consequence of lost or preserved walking ability, is limited.

Sarcopenia refers to a condition of progressive loss of skeletal muscle mass and function associated with a higher risk of falls and fractures in older adults. Musculoskeletal aging leads to reduced muscle mass and strength, affecting the quality of life in elderly people. In recent years, several studies contributed to improve the knowledge of the pathophysiological alterations that lead to skeletal muscle dysfunction; however, the molecular mechanisms underlying sarcopenia are still not fully understood. Muscle development and homeostasis require a fine gene expression modulation by mechanisms in which microRNAs (miRNAs) play a crucial role. miRNAs modulate key steps of skeletal myogenesis including satellite cells renewal, skeletal muscle plasticity, and regeneration. Here, we provide an overview of the general aspects of muscle regeneration and miRNAs role in skeletal mass homeostasis and plasticity with a special interest in their expression in sarcopenia and skeletal muscle adaptation to exercise in the elderly.

The interplay between chronic constraint and advanced aging on blood flow, shear-rate, vascular function, nitric oxide (NO)-bioavailability, microcirculation, and vascular inflammation factors is still a matter of debate. Ninety-eight individuals (Young, n = 28, 23 ± 3 yrs; Old, n = 36, 85 ± 7 yrs; Bedridden, n = 34, 88 ± 6 yrs) were included in the study. The bedridden group included old individuals chronically confined to bed (3.8 ± 2.3 yrs). A blood sample was collected and analyzed for plasma nitrate, and vascular inflammatory markers. Hyperemic response (∆peak) during the single passive leg movement (sPLM) test was used to measure vascular function. Skeletal muscle total hemoglobin was measured at the vastus lateralis during the sPLM test, by means of near infrared spectroscopy (NIRS). Bedridden subjects revealed a depletion of plasma nitrates compared with Old (−23.8%) and Young (−31.1%). Blood flow was lower in the Bedridden in comparison to Old (−20.1%) and Young (−31.7%). Bedridden presented lower sPLM ∆peak compared Old (−72.5%) and the Young (−83.3%). ∆peak of NIRS total hemoglobin was lower in the Bedridden compared to that in the Young (−133%). All vascular inflammatory markers except IL-6 were significantly worse in the Bedridden compared to Old and Young. No differences were found between the Old and Young in inflammatory markers. Results of this study confirm that chronic physical constraint induces an exacerbation of vascular disfunction and differential regulation of vascular-related inflammatory markers. The mechanisms involved in these negative adaptations seems to be associated with endothelial dysfunction and consequent diminished NO-bioavailability likely caused by the reduced shear-rate consequential to long-term reduction of physical activity.

Advanced aging, vascular dysfunction, and nitric oxide (NO) bioavailability are recognized risk factors for Alzheimer's disease (AD). However, the contribution of AD, per se, to this putative pathophysiological mechanism is still unclear. To better answer this point, we quantified cortical perfusion with arterial spin labeling (PVC-CBF), measured ultrasound internal carotid (ICA), and femoral (FA) artery blood flow in a group of patients with similar age (~78 years) but different cognitive impairment (i.e., mild cognitive impairment MCI, mild AD-AD1, moderate AD-AD2, and severe AD-AD3) and compared them to young and healthy old (aged-matched) controls. NO-metabolites and passive leg-movement (PLM) induced hyperemia were used to assess systemic vascular function. Ninety-eight individuals were recruited for this study. PVC-CBF, ICA, and FA blood flow were markedly (range of 9–17%) and significantly (all p < 0.05) reduced across the spectrum from YG to OLD, MCI, AD1, AD2, AD3 subjects. Similarly, plasma level of nitrates and the values of PLM were significantly reduced (range of 8–26%; p < 0.05) among the six groups. Significant correlations were retrieved between plasma nitrates, PLM and PVC-CBF, CA, and FA blood flow. This integrative and comprehensive approach to vascular changes in aging and AD showed progressive changes in NO bioavailability and cortical, extracranial, and peripheral circulation in patients with AD and suggested that they are directly associated with AD and not to aging. Moreover, these results suggest that AD-related impairments of circulation are progressive and not confined to the brain. The link between cardiovascular and the central nervous systems degenerative processes in patients at different severity of AD is likely related to the depletion of NO.

In western countries, aging is often accompanied by obesity and age-related obesity is characterized by vascular dysfunction and a low-grade inflammatory profile. Exercise is a nonpharmacological strategy able to decrease the development and incidence of risk factors for several health-threatening diseases. Nonetheless, its long-term effect on vascular function and inflammation in age-related obesity is still unclear. The aim of this study was to investigate the effect of regular, supervised exercise on inflammatory profile and vascular function in age-related obesity. We also hypothesized that vascular function and inflammatory profile would have been correlated in overweight and obese individuals. Thirty normal weight (NW; 70 ± 5 years, 23.9 ± 2.6 BMI) and forty overweight and obese elderly (OW&OB; 69 ± 5 years, 30.1 ± 2.3 BMI) regularly taking part in a structured, supervised exercise program were enrolled in the study and evaluated for vascular function (flow-mediated dilation; FMD) and inflammatory profile (plasma CRP, IL-1β, IL-1ra, IL-6, IL-8, IL-10, TNF-α, and MCP-1). Although no differences between groups were found concerning performance and the weekly amount of physical activity, the OW&OB group compared with the NW group demonstrated higher systolic and diastolic blood pressure (+10%, p=0.001; +9%, p=0.005, respectively); lower FMD% (−36%, p

Vasomotor response is related to the capacity of the vessel to maintain vascular tone within a narrow range. Two main control mechanisms are involved: the autonomic control of the sympathetic neural drive (global control) and the endothelial smooth cells capacity to respond to mechanical stress by releasing vasoactive factors (peripheral control). The aim of this study was to evaluate the effects of respiratory muscle training (RMT) on vasomotor response, assessed by flow-mediated dilation (FMD) and heart rate variability, in young healthy females. The hypothesis was that RMT could enhance the balance between sympathetic and parasympathetic neural drive and reduce vessel shear stress. Thus, twenty-four women were randomly assigned to either RMT or SHAM group. Maximal inspiratory mouth pressure and maximum voluntary ventilation were utilized to assess the effectiveness of the RMT program, which consisted of three sessions of isocapnic hyperventilation/ week for eight weeks, (twenty-four training sessions). Heart rate variability assessed autonomic balance, a global factor regulating the vasomotor response. Endothelial function was determined by measuring brachial artery vasodilation normalized by shear rate (%FMD/SR). After RMT, but not SHAM, maximal inspiratory mouth pressure and maximum voluntary ventilation increased significantly (+31% and +16%, respectively). Changes in heart rate variability were negligible in both groups. Only RMT exhibited a significant increase in %FMD/SR (+45%; p

ALU element instability could contribute to gene function variance in aging, and may partly explain variation in human lifespan.To assess the role of ALU element instability in human aging and the potential efficacy of ALU element content as a marker of biological aging and survival.Preliminary cohort study.We measured two high frequency ALU element subfamilies, ALU-J and ALU-Sx, by a single qPCR assay and compared ALU-J/Sx content in white blood cell (WBCs) and skeletal muscle cell (SMCs) biopsies from twenty-three elderly adults with sixteen healthy sex-balanced young adults; all-cause survival rates of elderly adults predicted by ALU-J/Sx content in both tissues; and cardiovascular disease (CVD)- and cancer-specific survival rates of elderly adults predicted by ALU-J/Sx content in both tissues, as planned subgroup analyses.We found greater ALU-J/Sx content variance in WBCs from elderly adults than young adults (P < 0.001) with no difference in SMCs (P = 0.94). Elderly adults with low WBC ALU-J/Sx content had worse four-year all-cause and CVD-associated survival than those with high ALU-J/Sx content (both P = 0.03 and hazard ratios (HR) ≥ 3.40), while WBC ALU-J/Sx content had no influence on cancer-associated survival (P = 0.42 and HR = 0.74). SMC ALU-J/Sx content had no influence on all-cause, CVD- or cancer -associated survival (all P ≥ 0.26; HR ≤ 2.07).These initial findings demonstrate that ALU element instability occurs with advanced age in WBCs, but not SMCs, and imparts greater risk of all-cause mortality that is likely driven by an increased risk for CVD and not cancer.

Recent literature highlights the importance of identifying factors associated with mild cognitive impairment (MCI) and Alzheimer’s Disease (AD). Actual validated biomarkers include neuroimaging and cerebrospinal fluid assessments; however, we investigated non-Aβ-dependent factors associated with dementia in 12 MCI and 30 AD patients. Patients were assessed for global cognitive function (Mini-Mental state examination—MMSE), physical function (Physical Performance Test—PPT), exercise capacity (6-min walking test—6MWT), maximal oxygen uptake (VO2max), brain volume, vascular function (flow-mediated dilation—FMD), inflammatory status (tumor necrosis factor—α ,TNF- α, interleukin-6, -10 and -15) and neurotrophin receptors (p75NTR and Tropomyosin receptor kinase A -TrkA). Baseline multifactorial information was submitted to two separate backward stepwise regression analyses to identify the variables associated with cognitive and physical decline in demented patients. A multivariate regression was then applied to verify the stepwise regression. The results indicated that the combination of 6MWT and VO2max was associated with both global cognitive and physical function (MMSE = 11.384 + (0.00599 × 6MWT) − (0.235 × VO2max)); (PPT = 1.848 + (0.0264 × 6MWT) + (19.693 × VO2max)). These results may offer important information that might help to identify specific targets for therapeutic strategies (NIH Clinical trial identification number NCT03034746).

Loss in body mass (∆BM) is a common feature in patients with Alzheimer's disease (AD). However, the etiology of this phenomenon is unclear. The aim of this cohort study was to observe possible ∆BM in AD patients following a standard institutionalized diet. Secondary objective was to identify possible predictors of ∆BM. To this end, 85 AD patients (age: 76±4 yrs; stature: 165±3 cm; BM: 61.6±7.4 kg; mean±standard deviation) and 86 controls (CTRL; age: 78±5 yrs; stature: 166±4 cm; BM: 61.7±6.4 kg) were followed during one year of standard institutionalized diet (~1800 kcal/24h). BM, daily energy expenditure, albuminemia, number of medications taken, and cortisolism, were recorded PRE and POST the observation period. Potential predictors of ∆BM in women (W) and men (M) with AD were calculated with a forward stepwise regression model. After one year of standard institutionalized diet, BM decreased significantly in AD (-2.5 kg; p < 0.01), while in CTRL remained unchanged (-0.4 kg; p = 0.8). AD patients and CTRL exhibited similar levels of daily energy expenditure (~1625 kcal/24h). The combination of three factors, number of medications taken, albuminemia, and cortisolism, predicted ∆BM in W with AD. At contrary, the best predictor of ∆BM in M with AD was the cortisolism. Despite a controlled energy intake and similar energy expenditure, both W and M with AD suffered of ∆BM. Therefore, controlled diet did not prevent this phenomenon. The assessments of these variables may predict W and M with AD at risk of weight loss.

The association of lysosomal dysfunction and neurodegeneration has been documented in several neurodegenerative diseases, including Alzheimer’s Disease (AD). Herein, we investigate the association of lysosomal enzymes with AD at different stages of progression of the disease (mild and severe) or with mild cognitive impairment (MCI). We conducted a screening of two classes of lysosomal enzymes: glycohydrolases (β-Hexosaminidase, β-Galctosidase, β-Galactosylcerebrosidase, β-Glucuronidase) and proteases (Cathepsins S, D, B, L) in peripheral blood samples (blood plasma and PBMCs) from mild AD, severe AD, MCI and healthy control subjects. We confirmed the lysosomal dysfunction in severe AD patients and added new findings enhancing the association of abnormal levels of specific lysosomal enzymes with the mild AD or severe AD, and highlighting the difference of AD from MCI. Herein, we showed for the first time the specific alteration of β-Galctosidase (Gal), β-Galactosylcerebrosidase (GALC) in MCI patients. It is notable that in above peripheral biological samples the lysosomes are more sensitive to AD cellular metabolic alteration when compared to levels of Aβ-peptide or Tau proteins, similar in both AD groups analyzed. Collectively, our findings support the role of lysosomal enzymes as potential peripheral molecules that vary with the progression of AD, and make them useful for monitoring regenerative medicine approaches for AD.