Immunology of Aging: the Birth of Inflammaging.

The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.

Novel approach to analysis of the immune system using an ungated model of immune surface marker abundance to predict health outcomes.

Traditionally, the immune system is understood to be divided into discrete cell types that are identified via surface markers. While some cell type distinctions are no doubt discrete, others may in fact vary on a continum, and even within discrete types, differences in surface marker abundance could have functional implications. Here we propose a new way of looking at immune data, which is by looking directly at the values of the surface markers without dividing the cells into different subtypes. To assess the merit of this approach, we compared it with manual gating using cytometry data from the Singapore Longitudinal Aging Study (SLAS) database. We used two different neural networks (one for each method) to predict the presence of several health conditions. We found that the model built using raw surface marker abundance outperformed the manual gating one and we were able to identify some markers that contributed more to the predictions. This study is intended as a brief proof-of-concept and was not designed to predict health outcomes in an applied setting; nonetheless, it demonstrates that alternative methods to understand the structure of immune variation hold substantial progress.

Immunosenescence is both functional/adaptive and dysfunctional/maladaptive.

Alterations in the immune system with aging are considered to underlie many age-related diseases. However, many elderly individuals remain healthy until even a very advanced age. There is also an increase in numbers of centenarians and their apparent fitness. We should therefore change our unilaterally detrimental consideration of age-related immune changes. Recent data taking into consideration the immunobiography concept may allow for meaningful distinctions among various aging trajectories. This implies that the aging immune system has a homeodynamic characteristic balanced between adaptive and maladaptive aspects. The survival and health of an individual depends from the equilibrium of this balance. In this article, we highlight which parts of the aging of the immune system may be considered adaptive in contrast to those that may be maladaptive.

Proceedings of the Canadian Frailty Network Workshop: Identifying Biomarkers of Frailty to Support Frailty Risk Assessment, Diagnosis and Prognosis. Toronto, January 15, 2018.

The Canadian Frailty Network (CFN), a pan-Canadian not-for-profit organization funded by the Government of Canada through the Networks of Centres of Excellence Program, is dedicated to improving the care of older Canadians living with frailty. The CFN has partnered with the Canadian Longitudinal Study on Aging (CLSA) to measure potential frailty biomarkers in biological samples (whole blood, plasma, urine) collected in over 30,000 CLSA participants. CFN hosted a workshop in Toronto on January 15 2018, bringing together experts in the field of biomarkers, aging and frailty. The overall objectives of the workshop were to start building a consensus on potential frailty biomarker domains and identify specific frailty biomarkers to be measured in the CLSA biological samples. The workshop was structured with presentations in the morning to frame the discussions for the afternoon session, which was organized as a free-flowing discussion to benefit from the expertise of the participants. Participants and speakers were from Canada, Italy, Spain, United Kingdom and the United States. Herein we provide pertinent background information, a summary of all the presentations with key figures and tables, and the distillation of the discussions. In addition, moving forward, the principles CFN will use to approach frailty biomarker research and development are outlined. Findings from the workshop are helping CFN and CLSA plan and conduct the analysis of biomarkers in the CLSA samples and which will inform a follow-up data access competition.

Electron Beam Driven Generation of Frequency-Tunable Isolated Relativistic Subcycle Pulses.

We propose a novel scheme for frequency-tunable subcycle electromagnetic pulse generation. To this end a pump electron beam is injected into an electromagnetic seed pulse as the latter is reflected by a mirror. The electron beam is shown to be able to amplify the field of the seed pulse while upshifting its central frequency and reducing its number of cycles. We demonstrate the amplification by means of 1D and 2D particle-in-cell simulations. In order to explain and optimize the process, a model based on fluid theory is proposed. We estimate that using currently available electron beams and terahertz pulse sources, our scheme is able to produce millijoule-strong midinfrared subcycle pulses.

Association between malnutrition-inflammation score and risk of subsequent self-reported bone fractures in prevalent kidney transplant recipients.

Chronic inflammation and protein energy wasting (PEW) syndrome are common in kidney transplant recipients (KTR). The presence of inflammation and PEW syndrome can directly affect bone resorption and bone formation, leading to bone loss and fractures. We showed PEW is independently associated with new clinically detected bone fractures in prevalent KTR. INTRODUCTION: Kidney transplant recipients (KTR) have a 4-fold higher risk of fracture compared to the general population. Chronic inflammation and PEW syndrome are common in KTR and are associated with poor outcomes. We hypothesized that the Malnutrition-Inflammation Score (MIS), a validated measure of PEW, is associated with higher risk of bone fractures in KTR. METHODS: This prospective cohort study included 839 prevalent KTR from a Central European academic center. MIS, a semiquantitative instrument of PEW, was calculated at the study entry. Self-reported history of fractures was recorded during the 2-year follow-up period. The association between MIS and bone fractures was examined in logistic regression analyses with adjustment for age, gender, eGFR, smoking habits, history of pre-transplant bone fractures, and acute rejection. RESULTS: Mean age was 51 ± 13 years, and 56% of patients were males with median (interquartile range) transplant vintage 69 (38-112) months, estimated glomerular filtration rate 55 ± 21 ml/min/1.73 m2, and calculated MIS 3 (2-4) at enrollment. Fifty-five (7%) patients experienced self-reported bone fractures during the 2-year follow-up period. Higher MIS score showed linear association with increased risk of fracture. Each one-point higher MIS was associated with 23% higher risk of bone fractures (odds ratio (OR) and 95% CI 1.23, 1.12-1.34), which remained significant after multivariable adjustments (OR 1.17, 95% CI 1.06-1.29). CONCLUSION: The MIS is independently associated with new clinically detected bone fractures in prevalent KTR.

A cross-sectional comparison of brain glucose and ketone metabolism in cognitively healthy older adults, mild cognitive impairment and early Alzheimer's disease.

INTRODUCTION: Deteriorating brain glucose metabolism precedes the clinical onset of Alzheimer's disease (AD) and appears to contribute to its etiology. Ketone bodies, mainly ß-hydroxybutyrate and acetoacetate, are the primary alternative brain fuel to glucose. Some reports suggest that brain ketone metabolism is unchanged in AD but, to our knowledge, no such data are available for MCI. OBJECTIVE: To compare brain energy metabolism (glucose and acetoacetate) and some brain morphological characteristics in cognitively healthy older adult controls (CTL), mild cognitive impairment (MCI) and early AD. METHODS: 24 CTL, 20 MCI and 19AD of similar age and metabolic phenotype underwent a dual-tracer PET and MRI protocol. The uptake rate constants and cerebral metabolic rate of glucose (KGlu, CMRGlu) and acetoacetate (KAcAc, CMRAcAc) were evaluated with PET using [18F]-fluorodeoxyglucose ([18F]-FDG), a glucose analogue, and [11C]-acetoacetate ([11C]-AcAc), a ketone PET tracer. Regional brain volume and cortical thickness were evaluated by T1-weighted MRI. RESULTS: In AD compared to CTL, CMRGlu was ~11% lower in the frontal, parietal, temporal lobes and in the cingulate gyrus (p<0.05). KGlu was ~15% lower in these same regions and also in subcortical regions. In MCI compared to CTL, ~7% glucose hypometabolism was present in the cingulate gyrus. Neither regional nor whole brain CMRAcAc or KAcAc were significantly different between CTL and MCI or AD. Reduced gray matter volume and cortical thinning were widespread in AD compared to CTL, whereas, in MCI compared to CTL, volumes were reduced only in the temporal cortex and cortical thinning was most apparent in temporal and cingulate regions. DISCUSSION: This quantitative kinetic PET and MRI imaging protocol for brain glucose and acetoacetate metabolism confirms that the brain undergoes structural atrophy and lower brain energy metabolism in MCI and AD and demonstrates that the deterioration in brain energy metabolism is specific to glucose. These results suggest that a ketogenic intervention to increase energy availability for the brain is warranted in an attempt to delay further cognitive decline by compensating for the brain glucose deficit in MCI and AD.

Effect of Partially Screened Nuclei on Fast-Electron Dynamics.

We analyze the dynamics of fast electrons in plasmas containing partially ionized impurity atoms, where the screening effect of bound electrons must be included. We derive analytical expressions for the deflection and slowing-down frequencies, and show that they are increased significantly compared to the results obtained with complete screening, already at subrelativistic electron energies. Furthermore, we show that the modifications to the deflection and slowing down frequencies are of equal importance in describing the runaway current evolution. Our results greatly affect fast-electron dynamics and have important implications, e.g., for the efficacy of mitigation strategies for runaway electrons in tokamak devices, and energy loss during relativistic breakdown in atmospheric discharges.

Composition and organization of the pancreatic extracellular matrix by combined methods of immunohistochemistry, proteomics and scanning electron microscopy.

The epidemic expansion of diabetes is a major concern of public health. A promising treatment is the transplantation of islets of Langerhans isolated from the whole pancreas but the yields of islets isolation and the rates of successful engraftments still have to be improved to make this therapy effective. The extracellular matrix (ECM) of the pancreatic tissue is partially lost during the isolation process and a comprehensive knowledge of the pancreatic ECM composition and organization could identify targets to improve islets isolation and transplantation or highlight new therapeutics for pancreatic diseases. The organization, composition and three-dimensional architecture of the pancreatic ECM were analysed in mouse and pig by three different techniques. Laminin α-4 and ß-2 chains are localized by immunohistochemistry in the exocrine tissue and inside islets of mouse pancreas but not around islets that are surrounded by an ECM made of collagen type IV and type V. Collagen type I, III, and VI were identified by proteomics as specific constituents of the pig pancreatic ECM along with the low-abundance isoforms α3(IV) α4(IV) α5(IV) and α1(V) α2(V) α3(V) of collagen type IV and type V respectively. The three-dimensional ECM architecture is analysed on decellularized mouse pancreas by scanning electron microscopy and is organized in honeycomb structures made of thin ECM fibers assembled in thicker bundles. The combination of immunohistochemistry, proteomics and scanning electron microscopy gives complementary perspective on the pancreatic ECM composition and organization. It represents a valuable toolbox for deeper investigations of ECMs and proposes clues in tissue engineering of the pancreas.

Intracellular signalling pathways: targets to reverse immunosenescence.

Ageing is a very complex process, the result of the dysregulation of multiple systems interacting in many ways. A prominent change occurring with ageing is related to the architecture and functioning of the immune system, viewed commonly as detrimental and termed 'immunosenescence'. However, age-associated changes may also lead to increased function in certain respects, which can be viewed as adaptive. None the less, on balance it is well-recognized that immunosenescence is accompanied by the low-grade inflammation observed commonly in elderly people, which has been dubbed 'inflamm-ageing'. The exact cause and significance of all these changes is not clear, but there is a consensus that they are related to the occurrence of chronic non-infectious age-associated disease, as well as increased susceptibility to infections. Alterations to immune cell signalling may be a prominent cause of malfunctioning immunity. Emerging attempts to reverse immunosenescence have recently targeted the signalling pathways in various different cell types of the immune system. Here, we review and discuss alterations in the signalling pathways of immune cells with ageing and consider current targets and means to modulate altered functions. We discuss the potential dangers as well as the benefits of these interventions, and consider future approaches to this problem.

Main biomarkers associated with age-related plasma zinc decrease and copper/zinc ratio in healthy elderly from ZincAge study.

PURPOSE: Zinc (Zn) plays an essential role in many biological processes including immune response. Impaired Zn status promotes immune dysfunction, and it has been associated with enhanced chronic inflammation during aging. It has been suggested that the measurement of circulating Zn by itself could not reflect the real Zn status of an individual. It is therefore necessary to identify other determinants associated with plasma Zn to better understanding how physiopathological conditions during aging may affect the concentration of this metal. METHODS: We have investigated the association between Zn levels and some biomarkers in 1090 healthy elderly from five European countries to increase the accuracy in the assessment of the Zn status. Stepwise multivariate linear regression models were used to analyze the influence of factors such as age, dietary intake, inflammatory mediators, laboratory parameters and polymorphisms previously associated with Zn homeostasis. RESULTS: Plasma Zn decrement was most strongly predicted by age, while positive correlations were found with albumin, RANTES and Zn intake after adjustment for multiple confounders. HSP70 +1267 AA genotype was an independent factor associated with Zn plasma concentrations. Cu/Zn ratio was positively associated with markers of systemic inflammation and age and negatively associated with albumin serum levels. CONCLUSIONS: Our findings show the most important independent determinants of plasma Zn concentration and Cu/Zn ratio variability in elderly population and suggest that the decline with age of Zn circulating levels is more dependent on physiopathological changes occurring with aging rather than to its nutritional intake.

[Physical activity and cancer: Update and literature review]. / Activité physique et cancer : mise au point et revue de la littérature.

Physical activity is a key determinant of public health and contributes to decreasing the prevalence of many diseases. Cancer is the leading cause of death worldwide. Physical activity, accessible to the entire population, could prevent up to 25% of cancers, in addition to improving survival rates and quality of life in cancer patients. Physical activity acts via various mechanisms to slow or decrease tumor growth, including the production and bioavailability of sex hormones, insulin resistance and insulin secretion, and inflammation. In primary prevention, physical activity reduces breast cancer risk by 15-20% and colorectal cancer risk by 24%. All-cause mortality is reduced by 33% in cancer survivors who exercise. Health-related quality of life, fatigue and depression are enhanced by the practice of physical activity in cancer patients. In the general population, the global recommendations on physical activity for health, published by the World Health Organisation, are suggested as a means of primary prevention of cancer. In cancer patients, an adapted physical activity routine is promoted from the very beginning of patient care to decrease fatigue as well as improve tolerance and benefits of treatments.

Muscle Mass Index and Animal Source of Dietary Protein Are Positively Associated with Insulin Resistance in Participants of the NuAge Study.

OBJECTIVES: Contribute evidence towards the complex interrelationships of body composition, insulin sensitivity and protein intake independently from adiposity in an older population. DESIGN: This is a cross-sectional analysis of an existing dataset in which a literature-supported model linking together the variables of interest is tested using path analysis. SETTING: The loss of muscle mass has been implicated in the development of insulin resistance. We propose to test associations of muscle mass with insulin sensitivity and their respective associations with animal and vegetable sources of protein intake, independently from adiposity. PARTICIPANTS: Non-diabetic participants aged 68-82 years from the NuAge study with all available measures (n=441) were included. MEASUREMENTS: A model considering age, sex, chronic diseases, physical activity; smoking and sources of protein intake influencing body composition components and insulin sensitivity was created and tested with Path Analysis for their independent associations. Muscle mass index (MMI; kg/height in m2) and % body fat were derived from DXA and BIA. Insulin resistance was estimated by the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score and physical activity by the Physical Activity Scale for the Elderly (PASE) questionnaire. Protein intakes were obtained from three non-consecutive 24h-diet recalls. RESULTS: In the final model, direct positive associations were observed between HOMA-IR score and MMI (ß=0.42; 95%CI: 0.24; 0.6) and % body fat (ß=0.094; 95%CI: 0.07; 0.11). There were no direct associations between animal protein intake and MMI or with HOMA-IR. There was a significant direct negative association between plant protein intake and MMI (ß= -0.068; 95%CI: -0.13; -0.003) and significant indirect associations mediated through MMI and % body fat between HOMA-IR and animal protein intake (ß=0.0321; 95%CI: 0.01; 0.05), as well as plant protein intake (ß= -0.07; 95%CI: -0.1; 0.0). CONCLUSIONS: Our final model indicated that MMI and HOMA score were significantly positively associated. Protein intake sources were related to HOMA-IR score differently through MMI and % body fat, respectively.

Relationship of metabolic and endocrine parameters to brain glucose metabolism in older adults: do cognitively-normal older adults have a particular metabolic phenotype?

Our primary objective in this study was to quantify whole brain and regional cerebral metabolic rates of glucose (CMRg) in young and older adults in order to determine age-normalized reference CMRg values for healthy older adults with normal cognition for age. Our secondary objectives were to--(i) report a broader range of metabolic and endocrine parameters including body fat composition that could form the basis for the concept of a 'metabolic phenotype' in cognitively normal, older adults, and (ii) to assess whether medications commonly used to control blood lipids, blood pressure or thyroxine affect CMRg values in older adults. Cognition assessed by a battery of tests was normal for age and education in both groups. Compared to the young group (25 years old; n = 34), the older group (72 years old; n = 41) had ~14% lower CMRg (µmol/100 g/min) specifically in the frontal cortex, and 18% lower CMRg in the caudate. Lower grey matter volume and cortical thickness was widespread in the older group. These differences in CMRg, grey matter volume and cortical thickness were present in the absence of any known evidence for prodromal Alzheimer's disease (AD). Percent total body fat was positively correlated with CMRg in many brain regions but only in the older group. Before and after controlling for body fat, HOMA2-IR was significantly positively correlated to CMRg in several brain regions in the older group. These data show that compared to a healthy younger adult, the metabolic phenotype of a cognitively-normal 72 year old person includes similar plasma glucose, insulin, cholesterol, triglycerides and TSH, higher hemoglobin A1c and percent body fat, lower CMRg in the superior frontal cortex and caudate, but the same CMRg in the hippocampus and white matter. Age-normalization of cognitive test results is standard practice and we would suggest that regional CMRg in cognitively healthy older adults should also be age-normalized.

From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation.

Aging is accompanied by many physiological changes including those in the immune system. These changes are designated as immunosenescence indicating that age induces a decrease in immune functions. However, since many years we know that some aspects are not decreasing but instead are increasing like the pro-inflammatory activity by the innate immune cells, especially by monocytes/macrophages. Recently it became evident that these cells may possess a sort of memory called trained memory sustained by epigenetic changes occurring long after even in the absence of the initiator aggressor. In this review we are reviewing evidences that such changes may occur in aging and describe the relationship between inflamm-aging and immunosenescence as an adaptation/remodelling process leading on one hand to increased inflammation and on the other to decreased immune response (immune-paralysis) mastered by the innate immune system. These changes may collectively induce a state of alertness which assure an immune response even if ultimately resulting in age-related deleterious inflammatory diseases.

Effective critical electric field for runaway-electron generation.

In this Letter we investigate factors that influence the effective critical electric field for runaway-electron generation in plasmas. We present numerical solutions of the kinetic equation and discuss the implications for the threshold electric field. We show that the effective electric field necessary for significant runaway-electron formation often is higher than previously calculated due to both (1) extremely strong dependence of primary generation on temperature and (2) synchrotron radiation losses. We also address the effective critical field in the context of a transition from runaway growth to decay. We find agreement with recent experiments, but show that the observation of an elevated effective critical field can mainly be attributed to changes in the momentum-space distribution of runaways, and only to a lesser extent to a de facto change in the critical field.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Young porcine endocrine pancreatic islets cultured in fibrin and alginate gels show improved resistance towards human monocytes.

AIM: To investigate the protective function of alginate and fibrin gels used to embed porcine endocrine pancreatic islets towards human monocytes. METHODS: Groups of 200 islet equivalents from young pigs were embedded in either a fibrin or in an alginate gel, and as a control seeded in tissue culture polystyrene (TCPS) well plates. The islet cultures were incubated with 2×10(5) human monocytes for 24h. In addition, both islets and monocytes were separately cultured in TCPS, fibrin and alginate. Islet morphology, viability and function were investigated as well as the secretion of cytokines TNFα, IL-6, and IL-1ß. RESULTS: When freely-floating in TCPS, non-encapsulated islets were surrounded by monocytes and started to disperse after 24h. In fibrin, monocytes could be found in close proximity to embedded islets, indicating monocyte migration through the gel. In contrast, after 24h, few monocytes were found close to islets in alginate. Immunofluorescence staining and manual counting showed that integrin expression was higher in fibrin-embedded islet cultures. A TUNEL assay revealed elevated numbers of apoptotic cells for islets in TCPS wells compared to fibrin and alginate cultures. Insulin secretion was higher with islets embedded in fibrin and alginate when compared to non-encapsulated islets. TNFα, IL-6 and IL-1ß were found in high concentrations in the media of co-cultures and monocyte mono-culture in fibrin. CONCLUSION: Both alginate and fibrin provide key structural support and offer some protection for the islets towards human monocytes. Fibrin itself triggers the cytokine secretion from monocytes.