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Background: It has been suggested that the acute natural killer (NK) cell response to aerobic exercise might contribute to the tumor suppressor effect of regular exercise observed in preclinical studies. Moreover, because this response is modulated by exercise intensity, high-intensity intervals exercise (HIIE) might represent an interesting therapeutic approach in cancer patients. However, this immune response remains unstudied in cancer patients currently undergoing chemotherapy. Objective: To characterize the acute NK cell response following a moderate-intensity continuous aerobic exercise session (MOD), and a HIIE session in metastatic cancer patients treated with chemotherapy. Methods: Twelve cancer patients (45–65 years old) underwent a MOD and a duration and work-matched HIIE trial, in a block-randomized order. Peripheral blood mononuclear cells (PBMC) were isolated before, after and 1h after each trial. NK cell subsets were enumerated using flow cytometry and complete blood counts. The surface expression of the cytotoxic NK cell (cNK; CD56dimCD16+) subset was evaluated for its expression of the differentiation markers CD57 and CD158a, the activating receptor NKG2D, the immune checkpoints TIM-3 and PD-1, and the chemokine receptors CXCR3, CXCR4 and CCR2. Results: cNK cell blood counts increased immediately following MOD (p

Abstract Sepsis is a prevalent life-threatening condition related to a systemic infection, and with unresolved issues including refractory septic shock and organ failures. Endogenously released catecholamines are often inefficient to maintain blood pressure, and low reactivity to exogenous catecholamines with risk of sympathetic overstimulation is well documented in septic shock. In this context, apelinergics are efficient and safe inotrope and vasoregulator in rodents. However, their utility in a larger animal model as well as the limitations with regards to the enzymatic breakdown during sepsis, need to be investigated. The therapeutic potential and degradation of apelinergics in sepsis were tested experimentally and in a cohort of patients. (1) 36 sheep with or without fecal peritonitis-induced septic shock (a large animal experimental design aimed to mimic the human septic shock paradigm) were evaluated for hemodynamic and renal responsiveness to incremental doses of two dominant apelinergics: apelin-13 (APLN-13) or Elabela (ELA), and (2) 52 subjects (33 patients with sepsis/septic shock and 19 healthy volunteers) were investigated for early levels of endogenous apelinergics in the blood, the related enzymatic degradation profile, and data regarding sepsis outcome. APLN-13 was the only one apelinergic which efficiently improved hemodynamics in both healthy and septic sheep. Endogenous apelinergic levels early rose, and specific enzymatic breakdown activities potentially threatened endogenous apelin system reactivity and negatively impacted the outcome in human sepsis. Short-term exogenous APLN-13 infusion is helpful in stabilizing cardiorenal functions in ovine septic shock; however, this ability might be impaired by specific enzymatic systems triggered during the early time course of human sepsis. Strategies to improve resistance of APLN-13 to degradation and/or to overcome sepsis-induced enzymatic breakdown environment should guide future works.

Atherosclerosis is an immuno-inflammatory process underlying cardiovascular diseases. One of the main actors of this inflammation is monocytes, with the switch in their phenotypes and irregularities in their cytokine production. Objective: This study was aimed to investigate the nutraceutical potential of extra virgin olive oil (EVOO) on the inflammatory status of monocytes in participants showing different levels of cardiovascular risk. Methods: 43 participants 65–85 years old were recruited including 14 healthy, 12 dyslipidemic patients with hypercholesterolemia recently diagnosed, and 17 post-infarct patients. Participants from all groups were supplemented with EVOO (25 mL/day) for 6 months. IL-1β, IL-6, IL-10, TNF-α cytokine production, and monocyte phenotypes were investigated both at quiescent and at stimulated state by flow cytometry. Results: At the baseline (pre-intervention), dyslipidemic patients, compared to healthy and post-infarct participants, showed monocytes in an inflammatory state characterized by a significantly weaker IL-10 production. Our results do not show a significant modulation of the phenotype or IL-10, IL-6, and TNF-α production following a 6-month EVOO intake whether at quiescence or under stimulation. However, IL-1β is significantly increased by the intervention of EVOO in post-infarct patients. Paradoxically after the 6-month intervention, monocytes from dyslipidemic patients showed a significantly decreased secretion of IL-1β under LPS stimulation despite the increase observed at basal state. Conclusion: Our results show that 6-month EVOO intervention did not induce a monocyte phenotypic change or that this intervention significantly modifies cytokine production.

Summary: Critical transition theory suggests that complex systems should experience increased temporal variability just before abrupt state changes. We tested this hypothesis in 763 patients on long-term hemodialysis, using 11 biomarkers collected every two weeks and all-cause mortality as a proxy for critical transitions. We find that variability—measured by coefficients of variation (CVs)—increases before death for all 11 clinical biomarkers, and is strikingly synchronized across all biomarkers: the first axis of a principal component analysis on all CVs explains 49% of the variance. This axis then generates powerful predictions of mortality (HR95 = 9.7, p

This study aimed to determine the size and distribution of LDL and HDL particles in North African acute coronary syndrome (ACS) patients and to compare the level of small dense LDL (sdLDL) to other markers used in cardiovascular risk prediction. Methods: A total of 205 ACS patients and 100 healthy control subjects were enrolled. LDL particle size and LDL and HDL subclass distributions were measured using Quantimetric Lipoprint® linear polyacrylamide gel electrophoresis. Lipid ratios (total cholesterol, LDL cholesterol, non-HDL cholesterol, and HDL cholesterol) were determined to calculate the atherogenic index of plasma (AIP), the atherogenic coefficient (AC), Castelli’s Risk-I (CR-I), and Castelli’s Risk-II (CR-II). Receiver operating characteristic (ROC) curve analyses and area under the curve (AUC) were used to assess the predictive value of sdLDL as a marker for cardiovascular disease. Results: The ACS patients, compared to the healthy control subjects, displayed an alteration of LDL particle distribution, with a significant increase in sdLDL serum concentrations (0.303 ± 0.478 mmol/L vs. 0.0225 ± 0.043 mmol/L, respectively, p < 0.001). The sdLDL levels had a high discrimination accuracy [AUC = 0.847 ± 0.0353 (95% CI 0.778 to 0.916, p < 0.0001)]. The best predictive cutoff value of ACS determined with the maximum Youden index (J) [(sensitivity + specificity) − 1 = 0.60] was 0.038 mmol/L. A Spearman correlation analysis showed that sdLDL levels were moderately but significantly and positively correlated with AC and CR-I (r = 0.37, p < 0.001) and weakly but significantly correlated with PAI and CR-II; r = 0.32 (p < 0.001) and r = 0.30 (p < 0.008), respectively. The subclass distribution of HDL particles from ACS patients was also altered, with a decrease in large HDL particles and an increase in small HDL particles compared to HDL from healthy control subjects. Conclusion: Due to their high atherogenicity, sdLDL levels could be used as a valuable marker for the prediction cardiovascular events.

Abstract Background Fried’s Phenotype Model of Frailty (PMF) postulates that frailty is a syndrome. Features of a syndrome are a heterogeneous population that can be split into at least two classes, those presenting and those not presenting the syndrome. Syndromes are characterized by a specific mixture of signs and symptoms which increase in prevalence, from less to more severe classes. So far, the null hypothesis of homogeneity – signs and symptoms of frailty cannot identify at least two classes – has been tested using Latent Class Analysis (LCA) on the five dichotomized components of PMF (unintentional weight loss, exhaustion, weakness, slowness, and low physical activity). The aim of this study is to investigate further the construct validity of frailty as a syndrome using the extension offered by Factor Mixture Models (FMM). Methods LCA on dichotomized scores and FMM on continuous scores were conducted to test homogeneity on the five PMF components in a sample of 1643 community-dwelling older adults living in Québec, Canada (FRéLE). Results With dichotomized LCA, three frailty classes were found: robust, prefrail and frail, and the hypothesis of homogeneity was rejected. However, in FMM, frailty was better represented as a continuous variable than as latent heterogeneous classes. Thus, the PMF measurement model of frailty did not meet the features of a syndrome in this study. Conclusion Using the FRéLE cohort, the PMF measurement model validity is questioned. Valid measurement of a syndrome depends on an understanding of its etiological factors and pathophysiological processes, and on a modelling of how the measured components are linked to these processes. Without these features, assessing frailty in a clinical setting may not improve patient health. Research on frailty should address these issues before promoting its use in clinical settings.

There is an increasingly widespread use of biomarkers in network physiology to evaluate an organism’s physiological state. A recent study showed that albumin variability increases before death in chronic hemodialysis patients. We hypothesized that a multivariate statistical approach would better allow us to capture signals of impending physiological collapse/death. We proposed a Moving Multivariate Distance (MMD), based on the Mahalanobis distance, to quantify the variability of the multivariate biomarker profile as a whole from one visit to the next. Biomarker profiles from a visit were used as the reference to calculate MMD at the subsequent visit. We selected 16 biomarkers (of which 11 are measured every 2 weeks) from blood samples of 763 chronic kidney disease patients hemodialyzed at the CHUS hospital in Quebec, who visited the hospital regularly (∼every 2 weeks) to perform routine blood tests. MMD tended to increase markedly preceding death, indicating an increasing intraindividual multivariate variability presaging a critical transition. In survival analysis, the hazard ratio between the 97.5th percentile and the 2.5th percentile of MMD reached as high as 21.1 [95% CI: 14.3, 31.2], showing that higher variability indicates substantially higher mortality risk. Multivariate approaches to early warning signs of critical transitions hold substantial clinical promise to identify early signs of critical transitions, such as risk of death in hemodialysis patients; future work should also explore whether the MMD approach works in other complex systems (i.e., ecosystems, economies), and should compare it to other multivariate approaches to quantify system variability.

Cancer-related fatigue (CRF) is a major issue in older cancer patients as it is associated with functional decline and a lower quality of life, and an increased inflammatory activity during cancer therapy is suspected to play a key role in CRF etiology. Combined aerobic and resistance exercise training is known to reduce CRF, and this could be mediated by a protective effect against this increased inflammatory activity. Hence, the main objective was to measure the effect of a 12-week combined exercise training on the inflammatory profile of older cancer patients undergoing systemic therapy. A secondary objective was to verify if there was an association between inflammatory profile and CRF. Methods: Twenty older non-metastatic cancer patients initiating chemotherapy and/or hormone therapy were randomly assigned to 12 weeks of supervised, combined exercise or a control group (static stretching). Primary outcomes were the inflammatory profile, Indoleamine 2,3-deoxygenase activity (KYN/TRP ratio), and CRF (FACIT-F questionnaire). Control outcomes were the fasting nutritional and hormonal blood profiles, body composition (iDXA), physical activity habits (PASE questionnaire), nutritional habits (3-day log), and treatment-related variables. Results: No worsening of the inflammatory profile was observed in both arms of the study after the intervention. No significant change in CRF was observed, although there was a trend for a reduction in the experimental group (p ​= ​0.10). Significant correlations were found at both timepoints between the KYN/TRP ratio and the delay with the previous treatment received (p ​≤ ​0.03). Conclusion: These results suggest that exercise might have elicited a positive effect on CRF, which was not mediated by the modulation of the pro-inflammatory cytokine profile. However, the decrease in IL-6/IL-10 ratio in the exercise group might reflect a possible anti-inflammatory effect of exercise. Moreover, exploratory analyses suggest that an acute effect of chemotherapy treatments influenced the inflammatory profile measurements, which could explain the absence of change in the fasting inflammatory profile.

We describe a network-based method to obtain a subset of representative variables from clinical data of subjects of the second Singapore Longitudinal Aging Study (SLAS-2), while preserving to a good extent the predictive performance of the full set with regards to a multi-faceted index of successful aging, SAGE. To examine differences in predictive performance of high-degree nodes ("hubs") and high-centrality ones ("cores"), we implement four subsetting strategies (two degree-based, two centrality-based) and obtain four surrogate sets of variables, which we use as input features for machine learning models to predict the SAGE index of subjects. All four models have variables belonging to the physical, cardiovascular, cognitive and immunological domains among their fifteen most important predictors. A fifth domain (leisure-time activities, LTA) is also present in some form. From a comparison of the surrogate sets' size and predictive performance, a centrality-based approach (selection of the most central variable-nodes within each cluster) yielded the smallest-sized surrogate set, while having high prediction accuracy (measured by its model's area-under-curve, AUC) in comparison to its analogous degree-based strategy (selection of the highest-degree nodes per cluster). Inclusion of the next most-central variables yielded negligible changes in predictive performance while more than doubling the surrogate set size. The centrality-based approach thus yields a surrogate set which offers a good balance between number of variables and prediction performance, and can act as a representative subset of the SLAS-2 clinical dataset.

We aimed to longitudinally assess the relationship between changing brain energy metabolism (glucose and acetoacetate) and cognition during healthy aging. Participants aged 71 ± 5 year underwent cognitive evaluation and quantitative positron emission tomography (PET) and magnetic resonance imaging (MRI) scans at baseline (N = 25) and two (N = 25) and four (N = 16) years later. During the follow-up, the rate constant for brain extraction of glucose (Kglc) declined by 6%–12% mainly in the temporo-parietal lobes and cingulate gyri (p ≤ 0.05), whereas brain acetoacetate extraction (Kacac) and utilization remained unchanged in all brain regions (p ≥ 0.06). Over the 4 years, cognitive results remained within the normal age range but an age-related decline was observed in processing speed. Kglc in the caudate was directly related to performance on several cognitive tests (r = +0.41 to +0.43, allp ≤ 0.04). Peripheral insulin resistance assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) was significantly inversely related to Kglc in the thalamus (r = −0.44, p = 0.04) and in the caudate (r = −0.43, p = 0.05), and also inversely related to executive function, attention and processing speed (r = −0.45 to −0.53, all p ≤ 0.03). We confirm in a longitudinal setting that the age-related decline in Kglc is directly associated with declining performance on some tests of cognition but does not significantly affect Kacac.

This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer’s disease (AD). Prof. Itzhaki presented her work on the role of viruses, specifically HSV-1, in the pathogenesis of AD. She maintains that although it is true that most people harbor HSV-1 infection, either latent or active, nonetheless aspects of herpes infection can play a role in the pathogenesis of AD, based on extensive experimental evidence from AD brains and infected cell cultures. Dr. Miklossy presented research on the high prevalence of bacterial infections that correlate with AD, specifically spirochete infections, which have been known for a century to be a significant cause of dementia (e.g., in syphilis). She demonstrated how spirochetes drive senile plaque formation, which are in fact biofilms. Prof. Balin then described the involvement of brain tissue infection by the Chlamydia pneumoniae bacterium, with its potential to use the innate immune system in its spread, and its initiation of tissue damage characteristic of AD. Prof. Fülöp described the role of AD-associated amyloid beta (Aβ) peptide as an antibacterial, antifungal and antiviral innate immune effector produced in reaction to microorganisms that attack the brain. Prof. Barron put forward the novel hypothesis that, according to her experiments, there is strong sequence-specific binding between the AD-associated Aβ and another ubiquitous and important human innate immune effector, the cathelicidin peptide LL-37. Given this binding, LL-37 expression in the brain will decrease Aβ deposition via formation of non-toxic, soluble Aβ/LL-37 complexes. Therefore, a chronic underexpression of LL-37 could be the factor that simultaneously permits chronic infections in brain tissue and allows for pathological accumulation of Aβ. This first-of-its-kind symposium opened the way for a paradigm shift in studying the pathogenesis of AD, from the “amyloid cascade hypothesis,” which so far has been quite unsuccessful, to a new “infection hypothesis,” or perhaps more broadly, “innate immune system dysregulation hypothesis,” which may well permit and lead to the discovery of new treatments for AD patients.

Alzheimer disease (AD) is the most prevalent form of dementia although the underlying cause(s) remains unknown at this time. However, neuroinflammation is believed to play an important role and suspected contributing immune parameters can be revealed in studies comparing patients at the stage of amnestic mild cognitive impairment (aMCI) to healthy age-matched individuals. A network of immune regulatory cells including regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) maintains immune homeostasis but there are very few data on the role of these cells in AD. Here, we investigated the presence of these cells in the blood of subjects with aMCI and mild AD (mAD) in comparison with healthy age-matched controls. We also quantitated several pro- and anti-inflammatory cytokines in sera which can influence the development and activation of these cells. We found significantly higher levels of MDSCs and Tregs in aMCI but not in mAD patients, as well as higher serum IL-1β levels. Stratifying the subjects based on CMV serostatus that is known to influence multiple immune parameters showed an absence of differences between aMCI subjects compared to mAD patients and healthy controls. We suggest that the increase in MDSCs and Tregs number in aMCI subjects may have a beneficial role in modulating inflammatory processes. However, this protective mechanism may have failed in mAD patients, allowing progression of the disease. This working hypothesis obviously requires testing in future studies.

Many studies of aging examine biomarkers one at a time, but complex systems theory and network theory suggest that interpretations of individual markers may be context-dependent. Here, we attempted to detect underlying processes governing the levels of many biomarkers simultaneously by applying principal components analysis to 43 common clinical biomarkers measured longitudinally in 3694 humans from three longitudinal cohort studies on two continents (Women's Health and Aging I & II, InCHIANTI, and the Baltimore Longitudinal Study on Aging). The first axis was associated with anemia, inflammation, and low levels of calcium and albumin. The axis structure was precisely reproduced in all three populations and in all demographic sub-populations (by sex, race, etc.); we call the process represented by the axis "integrated albunemia." Integrated albunemia increases and accelerates with age in all populations, and predicts mortality and frailty--but not chronic disease--even after controlling for age. This suggests a role in the aging process, though causality is not yet clear. Integrated albunemia behaves more stably across populations than its component biomarkers, and thus appears to represent a higher-order physiological process emerging from the structure of underlying regulatory networks. If this is correct, detection of this process has substantial implications for physiological organization more generally.

The incidence of atherosclerosis and related diseases increases with age. The aging process may enhance lipoprotein modification, which leads to an increase in the susceptibility of low density lipoprotein (LDL) and high density lipoprotein (HDL) to oxidation. Dehydroepiandrosterone (DHEA), the most abundant steroid hormone in humans, has been shown to have antiatherogenic effects. This hormone also decreases dramatically with age. In the present study, we were interested in determining the presence of DHEA/DHEAS (dehydroepiandrosterone sulfate) and changes in their concentrations in HDL and LDL lipoproteins with age. Moreover, we studied the susceptibility of LDL to oxidation with age in the presence or absence of vitamin E or DHEA. We demonstrated that vitamin E is unable to restore the decreased resistance to oxidation of LDL from elderly subjects to that of LDL obtained from young subjects. Furthermore, our results provide evidence that DHEA is an integral part of LDL and HDL and disappears to almost nondetectable levels during aging. The DHEA incorporated into the LDL from elderly subjects increased LDL resistance to oxidation in a concentration-dependent manner. The increased resistance provided by DHEA was higher than that with vitamin E. DHEA seems to act either by protecting vitamin E from disappearance from LDL under oxidation or by scavenging directly the free radicals produced during the oxidative process. Our results suggest that DHEA exerts an antioxidative effect on LDL, which could have antiatherogenic consequences. Careful clinical trials of DHEA replacement should determine whether this ex vivo effect could be translated into any measurable antiatherogenic (cardioprotective) action.—A. Khalil, J-P. Fortin, J-G. LeHoux, and T. Fülöp. Age-related decrease of dehydroepiandrosterone concentrations in low density lipoproteins and its role in the susceptibility of low density lipoproteins to lipid peroxidation. J. Lipid Res. 2000. 41: 1552–1561.

Background: Comirnaty, Pfizer-BioNTech's polyethylene-glycol (PEG)-containing Covid-19 vaccine, can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis in a small fraction of immunized people. A causal role of anti-PEG antibodies (Abs) has been proposed, but causality has not yet proven in an animal model. The aim of this study was to provide such evidence using pigs immunized against PEG, which displayed very high levels of anti-PEG antibodies (Abs). We also aimed to find evidence for a role of complement activation and thromboxane A2 release in blood to explore the mechanism of anaphylaxis. Methods: Pigs (n = 6) were immunized with 0.1 mg/kg PEGylated liposome (Doxebo) i.v., and the rise of anti-PEG IgG and IgM were measured in serial blood samples with ELISA. After ∼2–3 weeks the animals were injected i.v. with 1/3 human dose of the PEGylated mRNA vaccine, Comirnaty, and the hemodynamic (PAP, SAP) cardiopulmonary (HR, EtCO2,), hematological (WBC, granulocyte, lymphocyte and platelet counts) parameters and blood immune mediators (anti-PEG IgM and IgG antibodies, thromboxane B2, C3a) were measured as endpoints of HSRs (anaphylaxis). Results: The level of anti-PEG IgM and IgG rose 5–10-thousand-fold in all of 6 pigs immunized with Doxebo by day 6, after which time all animals developed anaphylactic shock to i.v. injection of 1/3 human dose of Comirnaty. The reaction, starting within 1 min involved maximal pulmonary hypertension and decreased systemic pulse pressure amplitude, tachycardia, granulo- and thrombocytopenia, and skin reactions (flushing or rash). These physiological changes or their absence were paralleled by C3a and TXB2 rises in blood. Conclusions: Consistent with previous studies, these data show a causal role of anti-PEG Abs in the anaphylaxis to Comirnaty, which involves complement activation, and, hence, it represents C activation-related pseudo-anaphylaxis. The setup provides the first large-animal model for mRNA-vaccine-induced anaphylaxis in humans.

Abstract This paper will update care providers on the clinical and scientific aspects of frailty which affects an increasing proportion of older people living with HIV (PLWH). The successful use of combination antiretroviral therapy has improved long-term survival in PLWH. This has increased the proportion of PLWH older than 50 to more than 50% of the HIV population. Concurrently, there has been an increase in the premature development of age-related comorbidities as well as geriatric syndromes, especially frailty, which affects an important minority of older PLWH. As the number of frail older PLWH increases, this will have an important impact on their health care delivery. Frailty negatively affects a PLWH’s clinical status, and increases their risk of adverse outcomes, impacting quality of life and health-span. The biologic constructs underlying the development of frailty integrate interrelated pathways which are affected by the process of aging and those factors which accelerate aging. The negative impact of sarcopenia in maintaining musculoskeletal integrity and thereby functional status may represent a bidirectional interaction with frailty in PLWH. Furthermore, there is a growing body of literature that frailty states may be transitional. The recognition and management of related risk factors will help to mitigate the development of frailty. The application of interdisciplinary geriatric management principles to the care of older PLWH allows reliable screening and care practices for frailty. Insight into frailty, increasingly recognized as an important marker of biologic age, will help to understand the diversity of clinical status occurring in PLWH, which therefore represents a fundamentally new and important aspect to be evaluated in their health care.

Aging is an important risk factor for cardiovascular diseases and convincing data have shown that chronic low-grade inflammation, which develops with advanced age, contributes significantly to cardiovascular risk. The present study aimed to use 18F-FDG/18F-NaF-PET/CT imaging to, respectively, gauge arterial inflammation and microcalcification in a healthy elderly population and to assess the potential benefits of a tyrosol- and hydroxytyrosol-rich diet on these two markers of atherosclerotic plaque fragility. Eleven healthy participants (mean age 75 ± 5.67 years) were supplemented for 6 months with high polyphenol-rich extra virgin olive oil (HP-EVOO), extra virgin olive oil (EVOO), or refined olive oil (ROO). The participants underwent PET/CT imaging with 18F-FDG and 18F-NaF radiotracers at baseline and after 6 months. 18F-FDG and 18F-NaF uptakes were quantified using standardized uptake values (SUV) and were categorized based on artery calcification and olive oil type. A total of 324 slices of the aortas of the imaged participants were analyzed for arterial inflammation and 327 slices were analyzed for microcalcification. 18F-FDG uptake was significantly higher in the non-calcified segments than in the calcified segments (SUVmax = 2.70 ± 0.62 and SUVmax = 2.54 ± 0.44, respectively, p < 0.042). Conversely, the non-calcified segments displayed significantly lower 18F-NaF uptake than the calcified segments (SUVmax = 1.90 ± 0.37 and 2.09 ± 0.24, respectively, p < 0.0001). The 6-month supplementation with HP-EVOO induced a significant reduction in 18F-FDG uptake in both the non-calcified (2.93 ± 0.23 to 2.75 ± 0.38, p < 0.004) and calcified segments of the aortas (2.25 ± 0.29 to 2.15 ± 0.19, p < 0.02). 18F-NaF uptake was also significantly lower in patients supplemented with HP-EVOO (SUVmax = 1.98 ± 0.33 at baseline compared to 1.85 ± 0.28, after the 6-month supplementation, p < 0.004), whereas no significant effect was observed with EVOO. Conversely, participants supplemented with ROO displayed a significant increase in 18F-NaF uptake (SUVmax = 1.78 ± 0.34 to 1.95 ± 0.34, p < 0.0001). The present study confirmed that a phenolic-compound-rich diet reduces both arterial inflammation and atherosclerotic lesion microcalcification and demonstrated that 18F-FDG/18F-NaF-PET/CT imaging is a valuable approach for assessing age-related arterial damage.

Modern research achievements support the health-promoting effects of natural products and diets rich in polyphenols. Pomegranate (PG) (Punica granatum L.) contains a considerable number of bioactive compounds that exert a broad spectrum of beneficial biological activities, including antimicrobial, antidiabetic, antiobesity, and atheroprotective properties. In this context, the reviewed literature shows that PG intake might reduce insulin resistance, cytokine levels, redox gene expression, blood pressure elevation, vascular injuries, and lipoprotein oxidative modifications. The lipid parameter corrective capabilities of PG-ellagitannins have also been extensively reported to be significantly effective in reducing hyperlipidemia (TC, LDL-C, VLDL-C, and TAGs), while increasing plasma HDL-C concentrations and improving the TC/HDL-C and LDL-C/HDL-C ratios. The health benefits of pomegranate consumption seem to be acheived through the amelioration of adipose tissue endocrine function, fatty acid utilization, GLUT receptor expression, paraoxonase activity enhancement, and the modulation of PPAR and NF-κB. While the results from animal experiments are promising, human findings published in this field are inconsistent and are still limited in several aspects. The present review aims to discuss and provide a critical analysis of PG’s bioeffects on the components of metabolic syndrome, type-2 diabetes, obesity, and dyslipidemia, as well as on certain cardiovascular-related diseases. Additionally, a brief overview of the pharmacokinetic properties, safety, and bioavailability of PG-ellagitannins is included.

BackgroundSarcopenia is common among older individuals with and without type 2 diabetes mellitus (T2DM). There are conflicting evidence in support of the role of insulin in the development of age-related and T2DM-related sarcopenia. We investigated the relationships between the levels of fasting insulin and other blood biomarkers related to insulin or lipid metabolism with the presence of sarcopenia in two independent studies.Materials and methodsIn 246 pre-frail frail older individuals with (n = 41) and without T2DM (n = 205) in the Singapore Frailty Interventional Trial, sarcopenia was defined by low appendicular lean mass (ALM) relative to total body mass (skeletal muscle index, SMI = ALM/height2) and low lower limb strength or gait speed according to the Asian Working Group for Sarcopenia (AWGS) criteria released in 2019, and related to levels of fasting insulin and glucose, C-peptide, IGF-1, leptin, and active ghrelin. This investigation was validated in another independent study sample of 189 robust and pre-frail frail elderly in the Singapore Longitudinal Aging Study Wave 2 (SLAS-2).ResultsCompared to non-sarcopenic individuals, those with sarcopenia and possible sarcopenia showed significantly lower fasting insulin (p < 0.05) in pre-frail/frail and non-frail older individuals. Consistent trends of relationships were observed for serum levels of C-peptide, IGF-1, leptin, and active ghrelin. In multivariable logistic regression models, sarcopenia was independently associated with low insulin (p < 0.05). Levels of fasting insulin, C-peptide, and leptin were also significantly associated with BMI, SMI, knee extension strength, gait speed, and physical activity score.ConclusionDysregulated insulin secretion in diabetic and non-diabetic older individuals may play an important role in age-related and diabetes-related sarcopenia.

Abstract Background Alzheimer’s disease (AD) is the most common neurodegenerative disease ultimately manifesting as clinical dementia. Despite considerable effort and ample experimental data, the role of neuroinflammation related to systemic inflammation is still unsettled. While the implication of microglia is well recognized, the exact contribution of peripheral monocytes/macrophages is still largely unknown, especially concerning their role in the various stages of AD. Objectives AD develops over decades and its clinical manifestation is preceded by subjective memory complaints (SMC) and mild cognitive impairment (MCI); thus, the question arises how the peripheral innate immune response changes with the progression of the disease. Therefore, to further investigate the roles of monocytes/macrophages in the progression of AD we assessed their phenotypes and functions in patients at SMC, MCI and AD stages and compared them with cognitively healthy controls. We also conceptualised an idealised mathematical model to explain the functionality of monocytes/macrophages along the progression of the disease. Results We show that there are distinct phenotypic and functional changes in monocyte and macrophage populations as the disease progresses. Higher free radical production upon stimulation could already be observed for the monocytes of SMC patients. The most striking results show that activation of peripheral monocytes (hyperactivation) is the strongest in the MCI group, at the prodromal stage of the disease. Monocytes exhibit significantly increased chemotaxis, free radical production, and cytokine production in response to TLR2 and TLR4 stimulation. Conclusion Our data suggest that the peripheral innate immune system is activated during the progression from SMC through MCI to AD, with the highest levels of activation being in MCI subjects and the lowest in AD patients. Some of these parameters may be used as biomarkers, but more holistic immune studies are needed to find the best period of the disease for clinical intervention.

Background: Elevated levels of cardiac troponin T as measured by a high-sensitivity test (hscTnT) are common in geriatric patients with a large spectrum of comorbidities but without acute coronary syndrome (ACS). However, the relative contribution of individual comorbidities has never been clearly addressed. This study aimed to determine the relationship between hscTnT elevation as a response variable and individual comorbidities, and to estimate the impact of individual comorbidities on hscTnT elevation in geriatric patients free of ACS. Methods: A nonexperimental, retrospective, matched, longitudinal cohort study was designed to evaluate the files of 7062 geriatric patients (aged ≥ 65 years) without ACS. The hscTnT levels of the patients have already been measured in all evaluated medical records. The dataset was split into 2 groups (0 and 1) based on the individual comorbidity (0 and 1) and hscTnT levels (≤ 14 ng/L = 0 and > 14 ng/L = 1). Results: Our results show that although age was positively and significantly correlated with hscTnT (r = 0.17, P < 0.0001), the likelihood of experiencing elevated hscTnT levels in older individuals after having excluded ACS was related to the presence of comorbidities independently of their number (P < 0.0001). The regression coefficients (β) associated with renal insufficiency (0.71), cardiomyopathy (0.63), chronic obstructive pulmonary disease (0.30), diabetes (0.25), and anemia (0.22) indicated that there exists a significant association between these comorbidities and the elevated hscTnT levels (P < 0.001). The receiver operating characteristic curve for predictive modeling was estimated at 71% (P < 0.0001). Conclusions: Elevated hscTnT levels were mostly associated with renal insufficiency, cardiac myopathies, chronic obstructive pulmonary disease, diabetes, and anemia in geriatric patients without ACS. Developing guidelines to accurately evaluate hscTnT elevation in geriatric patients with comorbidities, without ACS, is clinically essential. Résumé: Contexte: Il arrive fréquemment que les patients âgés présentant un grand éventail d’affections concomitantes, mais pas de syndrome coronarien aigu (SCA), aient un taux élevé de troponine T cardiaque mesuré par un test de haute sensibilité (TnTc-hs). La contribution relative des différentes affections concomitantes prises individuellement n’a toutefois jamais été clairement évaluée. Cette étude a tenté de déterminer la relation entre l’élévation du taux de TnTc-hs en tant que variable réponse et différentes affections concomitantes, et d’estimer l’effet individuel de ces affections concomitantes sur le taux de TnTc-hs chez les patients âgés exempts de SCA. Méthodologie: Nous avons conçu une étude de cohorte longitudinale, non expérimentale, rétrospective et avec appariement afin d’évaluer les dossiers de 7 062 patients âgés (≥ 65 ans) ne présentant pas de SCA. Les taux de TnTc-hs des patients avaient déjà été mesurés et figuraient dans tous les dossiers médicaux examinés. Les données ont été séparées en 2 groupes (0 et 1) en fonction de la présence d’une affection concomitante particulière (0 et 1) et du taux de TnTc-hs (≤ 14 ng/l = 0 et > 14 ng/l = 1). Résultats: Nos résultats indiquent que bien que l’âge soit corrélé de manière positive et significative avec le taux de TnTc-hs (r = 0,17, p < 0,0001), la probabilité qu’une personne âgée présente un taux de TnTc-hs élevé alors qu’un SCA a été exclu est liée à la présence d’affections concomitantes, indépendamment de leur nombre (p < 0,0001). Les coefficients de régression (β) associés à l’insuffisance rénale (0,71), à la cardiomyopathie (0,63), à la maladie pulmonaire obstructive chronique (0,30), au diabète (0,25) et à l’anémie (0,22) indiquent qu’il existe un lien significatif entre ces affections et un taux élevé de TnTc-hs (p < 0,001). La courbe caractéristique de la performance d’un test correspondant à la modélisation prédictive a été estimée à 71 % (p < 0,0001). Conclusions: Chez les patients âgés exempts de SCA, les taux élevés de TnTc-hs étaient principalement associés à l’insuffisance rénale, à la cardiomyopathie, à la maladie pulmonaire obstructive chronique, au diabète et à l’anémie. Il est donc essentiel, sur le plan clinique, d’établir des lignes directrices permettant de mesurer avec précision l’élévation du taux de TnTc-hs chez les patients âgés présentant des affections concomitantes, mais exempts de SCA.

Aging is associated with immune attrition that may impact the effectiveness of the immune system to protect the host from pathogens. Here the authors show that immune aging is associated with alterations in the Wnt/β-catenin signaling and reduced stem cell memory T lymphocytes, hinting the Wnt/β-catenin pathway as a potential therapy target.

Recent observations from clinical trials using monoclonal antibodies against Aβ seem to suggest that Aβ-targeting is modestly effective and not sufficiently based on an effective challenge of the role of Aβ from physiological to pathological. After an accelerated approval procedure for aducanumab, and more recently lecanemab, their efficacy and safety remain to be fully defined despite previous attempts with various monoclonal antibodies, and both academic institutions and pharmaceutical companies are actively searching for novel treatments. Aβ needs to be clarified further in a more complicated context, taking into account both its accumulation and its biological functions during the course of the disease. In this review, we discuss the border between activities affecting early, potentially reversible dysfunctions of the synapse and events trespassing the threshold of inflammatory, self-sustaining glial activation, leading to irreversible damage. We detail a clear understanding of the biological mechanisms underlying the derangement from function to dysfunction and the switch of the of Aβ role from physiological to pathological. A picture is emerging where the optimal therapeutic strategy against AD should involve a number of allied molecular processes, displaying efficacy not only in reducing the well-known AD pathogenesis players, such as Aβ or neuroinflammation, but also in preventing their adverse effects.

We have shown before that at least one intracellular proteolytic system seems to be at least as abundant in the peripheral blood lymphocytes of centenarians as in the same cells of young individuals (with the cells of the elderly population showing a significant dip compared to both young and centenarian cohorts). Despite scarce published data, in this review, we tried to answer the question how do different types of cells of longevous people—nonagenarians to (semi)supercentenarians—maintain the quality and quantity of their structural and functional proteins? Specifically, we asked if more robust proteodynamics participate in longevity. We hypothesized that at least some factors controlling the maintenance of cellular proteomes in centenarians will remain at the “young” level (just performing better than in the average elderly). In our quest, we considered multiple aspects of cellular protein maintenance (proteodynamics), including the quality of transcribed DNA, its epigenetic changes, fidelity and quantitative features of transcription of both mRNA and noncoding RNAs, the process of translation, posttranslational modifications leading to maturation and functionalization of nascent proteins, and, finally, multiple facets of the process of elimination of misfolded, aggregated, and otherwise dysfunctional proteins (autophagy). We also included the status of mitochondria, especially production of ATP necessary for protein synthesis and maintenance. We found that with the exception of the latter and of chaperone function, practically all of the considered aspects did show better performance in centenarians than in the average elderly, and most of them approached the levels/activities seen in the cells of young individuals.

High level of cardiac Troponin T (hs-cTnT) in geriatric population has been considered as an age-related phenomenon, which may question the interpretation of the increase of hs-cTnT in this population. The challenge is what is the primary cause of the increased hs-cTnT levels in elderly patients without AMI. Objective: The aim of the current study was to determine the impact of aging on hs-cTnT levels in elderly patients without acute cardiac events but in the presence of comorbidities. Methods: Sociodemographic and clinical data were collected from 6977 medical records of patients aged ≥65 years without acute coronary events but for whom hs-cTnT measurements were available. The patients were stratified based on age, troponin levels and the number of comorbidities. Results: The results suggested that the likelihood of increased hs-cTnT was related to the presence of comorbidities independently of their number (p

Background: Immune adaptation with aging is a major of health outcomes. Studies in humans have mainly focus on αβ T cells while γδ T cells have been neglected despite their role in immunosurveillance. We investigated the impact of aging on γδ T cell subsets phenotypes, functions, senescence and their molecular response to stress. Methods: Peripheral blood of young and old donors in Singapore have been used to assess the phenotype, functional capacity, proliferation capacity and gene expression of the various γδ T cell subsets. Peripheral blood mononuclear cells from apheresis cones and young donors have been used to characterize the telomere length, epigenetics profile and DNA damage response of the various γδ T cell subsets phenotype. Findings: Our data shows that peripheral Vδ2+ phenotype, functional capacity (cytokines, cytotoxicity, proliferation) and gene expression profile are specific when compared against all other αβ and γδ T cells in aging. Hallmarks of senescence including telomere length, epigenetic profile and DNA damage response of Vδ2+ also differs against all other αβ and γδ T cells. Interpretation: Our results highlight the differential impact of lifelong stress on γδ T cells subsets, and highlight possible mechanisms that enable Vδ2+ to be resistant to cellular aging. The new findings reinforce the concept that Vδ2+ have an “innate-like” behavior and are more resilient to the environment as compared to “adaptive-like” Vδ1+ T cells. Keywords: Gamma Delta T cells, Immunosenescence, Innate Immunity, Immunobiology, Aging, Cellular Senescence