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Significance: Chronic kidney disease (CKD) can be regarded as a burden of lifestyle disease that shares common underpinning features and risk factors with the aging process; it is a complex constituted by several adverse components, including chronic inflammation, oxidative stress, early vascular aging, and cellular senescence. Recent Advances: A systemic approach to tackle CKD, based on mitigating the associated inflammatory, cell stress, and damage processes, has the potential to attenuate the effects of CKD, but it also preempts the development and progression of associated morbidities. In effect, this will enhance health span and compress the period of morbidity. Pharmacological, nutritional, and potentially lifestyle-based interventions are promising therapeutic avenues to achieve such a goal. Critical Issues: In the present review, currents concepts of inflammation and oxidative damage as key patho-mechanisms in CKD are addressed. In particular, potential beneficial but also adverse effects of different systemic interventions in patients with CKD are discussed. Future Directions: Senotherapeutics, the nuclear factor erythroid 2-related factor 2-kelch-like ECH-associated protein 1 (NRF2-KEAP1) signaling pathway, the endocrine klotho axis, inhibitors of the sodium-glucose cotransporter 2 (SGLT2), and live bio-therapeutics have the potential to reduce the burden of CKD and improve quality of life, as well as morbidity and mortality, in this fragile high-risk patient group. Antioxid. Redox Signal. 35, 1426-1448.

Chronic kidney disease (CKD) manifests with systemic inflammation, oxidative stress, and gut dysbiosis, resulting in metabolic disorders and elevated rates of cardiovascular disease–associated death. These all correlate with a high economic cost to healthcare systems. Growing evidence indicates that diet is an indispensable ally in the prevention and management of CKD and its complications. In this context, the root vegetable beetroot (Beta vulgaris rubra) deserves special attention because it is a source of several bioactive compounds, such as nitrate, betaine, and betalain, and has shown beneficial effects in CKD, including reduction of blood pressure, anti-inflammatory effects, and antioxidant actions by scavenging radical oxidative species, as observed in preclinical studies. Beetroot consumption as a possible therapeutic strategy to improve the clinical treatment of patients with CKD and future directions for clinical studies are addressed in this narrative review.

Sulforaphane (SFN) is a sulfur-containing isothiocyanate found in cruciferous vegetables (Brassicaceae) and a well-known activator of nuclear factor-erythroid 2-related factor 2 (Nrf2), considered a master regulator of cellular antioxidant responses. Patients with chronic diseases, such as diabetes, cardiovascular disease, cancer, and chronic kidney disease (CKD) present with high levels of oxidative stress and a massive inflammatory burden associated with diminished Nrf2 and elevated nuclear transcription factor-κB-κB expression. Because it is a common constituent of dietary vegetables, the salutogenic properties of sulforaphane, especially it’s antioxidative and anti-inflammatory properties, have been explored as a nutritional intervention in a range of diseases of ageing, though data on CKD remain scarce. In this brief review, the effects of SFN as a senotherapeutic agent are described and a rationale is provided for studies that aim to explore the potential benefits of SFN-rich foods in patients with CKD.

The observation that unhealthy diets (those that are low in whole grains, fruits and vegetables, and high in sugar, salt, saturated fat and ultra-processed foods) are a major risk factor for poor health outcomes has boosted interest in the concept of 'food as medicine'. This concept is especially relevant to metabolic diseases, such as chronic kidney disease (CKD), in which dietary approaches are already used to ameliorate metabolic and nutritional complications. Increased awareness that toxic uraemic metabolites originate not only from intermediary metabolism but also from gut microbial metabolism, which is directly influenced by diet, has fuelled interest in the potential of 'food as medicine' approaches in CKD beyond the current strategies of protein, sodium and phosphate restriction. Bioactive nutrients can alter the composition and metabolism of the microbiota, act as modulators of transcription factors involved in inflammation and oxidative stress, mitigate mitochondrial dysfunction, act as senolytics and impact the epigenome by altering one-carbon metabolism. As gut dysbiosis, inflammation, oxidative stress, mitochondrial dysfunction, premature ageing and epigenetic changes are common features of CKD, these findings suggest that tailored, healthy diets that include bioactive nutrients as part of the foodome could potentially be used to prevent and treat CKD and its complications.

Chronic kidney disease (CKD) is a clinical model of premature ageing characterized by cardiovascular disease, persistent uraemic inflammation, osteoporosis muscle wasting and frailty. The accelerated early vascular ageing (EVA) process mediated by medial vascular calcification (VC) is a hallmark of senescence as well as a strong predictor of cardiovascular morbidity and mortality in the CKD population. Current clinical therapeutic strategies and novel treatments for VC have not yet been proven to prevent or reverse VC progression in patients with CKD. Knowledge of the fundamental mechanism underlying EVA is urgently needed to identify and develop novel and efficient therapeutic targets for VC and EVA. An accumulating body of evidence indicates that deoxyribonucleic acid (DNA) damage–induced cellular senescence and ‘inflammaging’ may largely contribute to such pathological conditions characterized by accelerated EVA. Growing evidence shows that nuclear factor erythroid 2–related factor 2 (NRF2) signalling and vitamin K play a crucial role in counteracting oxidative stress, DNA damage, senescence and inflammaging, whereby NRF2 activation and vitamin K supplementation may provide a novel treatment target for EVA. In this review we discuss the link between senescence and EVA in the context of CKD, with a focus on the role of NRF2 and vitamin K in DNA damage signalling, senescence and inflammaging.

A paradox of so-called developed countries is that, as the major historical causes of human mortality are eliminated or mitigated by medical progress, life-style related diseases have become major killers. Furthermore, as life-span is extended by the combined effects of modern medicine, health-span is struggling to keep apace because of the burden of non-communicable diseases linked to diet and sedentary life-style. The gut microbiome is now recognized as a plastic environmental risk factor for many of these diseases, the microbiome being defined as the complex community of co-evolved commensal microbes that breaks down components of a complex diet, modulates innate immunity, and produces signalling molecules and metabolites that can impact on diverse regulatory systems in mammals. Aspects of the so-called â Westernâ life-style linked to disease risk such as energy dense diet and antibiotic treatment are known to affect the composition and function of the microbiome. Here we review the detailed mechanisms whereby the gut microbiome may modulate risk of diseases linked to sedentary life-style, and ageing related health loss. We focus on the comparative value of natural animal models such as hibernation for studying metabolic regulation, and the challenge of extrapolating from animal models to processes that occur in human ageing.

Introduction Resistant starch type-2 (RS2) can mitigate inflammation and oxidative stress in hemodialysis (HD) patients. However, there is still a lack of knowledge on the impact of the RS2 on the gut microbiota community in these patients. Thus, this study aims to evaluate the effects of enriched RS2 cookies on the gut microbiome in HD patients. Methods and results This comprises a randomized, double-blind, placebo-controlled trial of age-, sex-, and BMI-matched patients and controls. The RS2 group receives enriched RS2 cookies (16 g d-1 of Hi-Maize 260, Ingredion) for 4 weeks, while the placebo group received cookies made with manioc flour. Fecal microbiota composition is evaluated by the 16S ribosomal RNA gene. Analysis of the microbiota reveals that Pielou's evenness is significantly decreased after RS2 supplementation. Notably, it is observed that RS2 intervention upregulates significantly 8 Amplicon Sequencing Variants (ASV's), including Roseburia and Ruminococcus gauvreauii, which are short-chain fatty acids (SCFA) producers. Furthermore, it is associated with the downregulation of 11 ASVs, such as the pro-inflammatory Dialister. Conclusions RS2 intervention for 4 weeks in HD patients effectively alters SCFA producers in the gut microbiota, suggesting that it could be a good nutritional strategy for patients with chronic kidney disease (CKD) on HD.

The cytoprotective transcriptor factor nuclear factor erythroid 2– related factor 2 (NRF2) is part of a complex regulatory network that responds to environmental cues. To better understand its role in a cluster of inflammatory and pro-oxidative burden of lifestyle diseases that accumulate with age, lessons can be learned from evolution, the animal kingdom and progeroid syndromes. When levels of oxygen increased in the atmosphere, mammals required ways to protect themselves from the metabolic toxicity that arose from the production of reactive oxygen species. The evolutionary origin of the NRF2–Kelch-like ECH-associated protein 1 (KEAP1) signalling pathway from primitive origins has been a prerequisite for a successful life on earth, with checkpoints in antioxidant gene expression, inflammation, detoxification and protein homoeostasis. Examples from the animal kingdom suggest that superior antioxidant defense mechanisms with enhanced NRF2 expression have been developed during evolution to protect animals during extreme environmental conditions, such as deep sea diving, hibernation and habitual hypoxia. The NRF2–KEAP1 signalling pathway is repressed in progeroid (accelerated ageing) syndromes and a cluster of burden of lifestyle disorders that accumulate with age. Compelling links exist between tissue hypoxia, senescence and a repressed NRF2 system. Effects of interventions that activate NRF2, including nutrients, and more potent (semi)synthetic NRF2 agonists on clinical outcomes are of major interest. Given the broad-ranging actions of NRF2, we need to better understand the mechanisms of activation, biological function and regulation of NRF2 and its inhibitor, KEAP1, in different clinical conditions to ensure that modulation of this thiol-based system will not result in major adverse effects. Lessons from evolution, the animal kingdom and conditions of accelerated ageing clarify a major role of a controlled NRF2–KEAP1 system in healthy ageing and well-being.

A systematic review following PRISMA guidelines was conducted to answer the question: What epigenetic, telomeric and associated biological changes are associated with exposure to adverse childhood experiences (ACEs) in the under 12s? Using PRISMA guidelines, appropriate databases were searched. 190 papers were returned with 38 articles fully reviewed. Articles were each independently quality rated by two authors using the Crowe Critical Appraisal Tool and data were extracted. Of the 38 articles, 23 were rated as very high quality. Most study participants were adults (n = 7769) with n = 727 child participants. Only seven of the very/high-quality studies were prospective and involved children. Methylation was the most studied method of epigenetic modification. There is some evidence supporting epigenetic modification of certain markers in participants exposed to ACEs measured in adulthood. Research is lacking on non-coding aspects of the epigenome and on coding aspects other than DNA methylation. There is some evidence of a more powerful effect on telomere length if physical neglect was involved. Much further work is required to model biological and psychological effects of epigenetic changes during childhood using prospective study designs. The effect of ACEs on the cellular ageing process during childhood is inadequately investigated and relies solely on measure of telomere length. Future research suggestions are proposed.

MicroRNAs are epigenetic regulators of gene expression at the posttranscriptional level. They are involved in intercellular communication and crosstalk between different organs. As key regulators of homeostasis, their dysregulation underlies several morbidities including kidney disease. Moreover, their remarkable stability in plasma and urine makes them attractive biomarkers. Beyond biomarker studies, clinical microRNA research in nephrology in recent decades has focused on the discovery of specific microRNA signatures and the identification of novel targets for therapy and/or disease prevention. However, much of this research has produced equivocal results and there is a need for standardization and confirmation in prospective trials. This review aims to provide an overview of general concepts and available clinical evidence in both the pathophysiology and biomarker fields for the role of microRNA in AKI and kidney transplantation.

Background and Aims Chronic kidney disease (CKD) shares important features of a dysregulated ageing process with other common “burden of lifestyle” diseases, which aggregates into the diseasome of ageing. Typically, this is hallmarked by an acceleration of epigenetic (DNA methylation-based) clocks. It remains to be determined if current therapeutic interventions, such as renal transplantation or dialysis, can slow this clock, and thus the rate of biological ageing, in CKD. We therefore assessed the rate of biological ageing in CKD patients and whether these therapies impact on it, by measuring epigenetic age before and 1 year after treatment. Methods Whole blood samples were taken from CKD 5 patients at baseline and 1 year after renal transplantation (n=12) or dialysis (n=11; peritoneal dialysis n=7, haemodialysis n=4) as well as from age and sex-matched population-based controls (n=24). DNA methylation was measured using the Illumina Infinium Human Methylation 450K BeadChip and epigenetic age was calculated using three independent DNA methylation clocks: the Horvath, Hannum, and PhenoAge clocks. Additionally, a novel composite clock incorporating these three clocks was evaluated. We then calculated the age acceleration (difference between epigenetic and chronological age) for each clock and compared average age acceleration between groups and across time points. Results Incident dialysis patients displayed accelerated ageing versus chronologically age-matched controls (p Conclusion CKD 5 patients display an increased biological (i.e. epigenetic) age. This age acceleration is mitigated one year after renal transplantation, but not in patients undergoing dialysis. Neither therapy reverses high biological age.

Eine chronische Nierenkrankheit (CKD) ist unter anderem durch einen vorzeitigen Alterungsprozess gekennzeichnet. Dies geht mit unterschwelligen Entzundungsvorgangen einher, die in ihrer Gesamtheit als „inflammageing“ bezeichnet werden. Bestimmte Bestandteile von Nahrungsmitteln konnen das „inflammageing“ vermindern und damit pathologische Alterungsprozesse im Rahmen von chronischen Krankheiten reduzieren. Diese Entwicklungen konnen eine wichtige Grundlage fur das Konzept „Lebensmittel als Medizin“ in der Nephrologie sein. Diese Ubersicht stellt die Zusammenhange zwischen der Nahrung und ihren Bestandteilen und pathologischen Alterungsprozessen, insbesondere im Hinblick auf das „inflammageing“ bei CKD, sowie moglichen Therapieansatzen dar.

Garlic, a member of the Allium family, widely used in cooking for many centuries, displays well described antioxidant and anti-inflammatory properties, as a result of its constituent organosulfur compounds, such as alliin, allicin, ajoene S-allyl-cysteine, diallyl sulfide and diallyl disulfide, among others. Although garlic has demonstrated beneficial effects in cardiovascular disease, diabetes, and cancer, its efficacy as a therapeutic intervention in chronic kidney disease remains to be proven. This review thus focuses on the potential benefits of garlic as a treatment option in chronic kidney disease. and its ability to mitigate associated cardiovascular complications and gut dysbiosis.

Patients treated with hemodialysis (HD) repeatedly undergo intradialytic low arterial oxygen saturation and low central venous oxygen saturation, reflecting an imbalance between upper body systemic oxygen supply and demand, which are associated with increased mortality. Abnormalities along the entire oxygen cascade, with impaired diffusive and convective oxygen transport, contribute to the reduced tissue oxygen supply. HD treatment impairs pulmonary gas exchange and reduces ventilatory drive, whereas ultrafiltration can reduce tissue perfusion due to a decline in cardiac output. In addition to these factors, capillary rarefaction and reduced mitochondrial efficacy can further affect the balance between cellular oxygen supply and demand. Whereas it has been convincingly demonstrated that a reduced perfusion of heart and brain during HD contributes to organ damage, the significance of systemic hypoxia remains uncertain, although it may contribute to oxidative stress, systemic inflammation, and accelerated senescence. These abnormalities along the oxygen cascade of patients treated with HD appear to be diametrically opposite to the situation in Tibetan highlanders and Sherpa, whose physiology adapted to the inescapable hypobaric hypoxia of their living environment over many generations. Their adaptation includes pulmonary, vascular, and metabolic alterations with enhanced capillary density, nitric oxide production, and mitochondrial efficacy without oxidative stress. Improving the tissue oxygen supply in patients treated with HD depends primarily on preventing hemodynamic instability by increasing dialysis time/frequency or prescribing cool dialysis. Whether dietary or pharmacological interventions, such as the administration of L-arginine, fermented food, nitrate, nuclear factor erythroid 2-related factor 2 agonists, or prolyl hydroxylase 2 inhibitors, improve clinical outcome in patients treated with HD warrants future research.

Propolis is a polyphenolic plant resin collected by bees to protect hives against pathogens and temperature drop. It exhibits antibacterial, antioxidant, and antiinflammatory properties. Propolis has been reported to possess antidiabetic properties and display beneficial effects against cardiovascular disease, gut dysbiosis, and chronic kidney disease. It has an excellent clinical safety profile, with no known toxic effects described so far. In this review, we discuss the salutogenic effects of propolis, with particular reference to modulating notable features of chronic kidney disease, notably those involving cardiovascular risks.

Klotho has been recognized as a gene involved in the aging process in mammals for over 30 years, where it regulates phosphate homeostasis and the activity of members of the fibroblast growth factor (FGF) family. The α-Klotho protein is the receptor for Fibroblast Growth Factor-23 (FGF23), regulating phosphate homeostasis and vitamin D metabolism. Phosphate toxicity is a hallmark of mammalian aging and correlates with diminution of Klotho levels with increasing age. As such, modulation of Klotho activity is an attractive target for therapeutic intervention in the diseasome of aging; in particular for chronic kidney disease (CKD), where Klotho has been implicated directly in the pathophysiology. A range of senotherapeutic strategies have been developed to directly or indirectly influence Klotho expression, with varying degrees of success. These include administration of exogenous Klotho, synthetic and natural Klotho agonists and indirect approaches, via modulation of the foodome and the gut microbiota. All these approaches have significant potential to mitigate loss of physiological function and resilience accompanying old age and to improve outcomes within the diseasome of aging.

No abstract available.

Background and Aims While chronological age associates with increased risk of death, there is a quest for markers of biological age in chronic kidney disease (CKD) that better reflect accumulation of tissue and cellular damage, which could contribute to shorter life span. Skin autofluorescence (SAF) is a biomarker for accumulation of advanced glycation end products in skin that associate with chronological age and with factors that may increase mortality risk. However, the predictive capacity of SAF for mortality has not been fully elucidated in CKD. We have investigated the relationship between biological age calculated by SAF, chronological age and all-cause mortality in patients with CKD stage 5. Method In a cohort of 199 CKD5 patients (non-dialysis CKD5, n=100, hemodialysis, n=27 and peritoneal dialysis, n=72; median age 66 years, 34% females, 21% diabetes (DM), 20% cardiovascular disease (CVD), and 34% malnourished), we calculated biological age by a formula based on SAF measurements using the AGE Reader. Framingham risk score, coronary artery calcium score, the heart rate-corrected augmentation index, body composition, nutritional status, handgrip strength, and various biochemical markers (hemoglobin, albumin, creatinine, intact-parathyroid hormone, triglyceride, cholesterol, HDL-cholesterol, high-sensitivity C-reactive protein (hsCRP), and interleukin (IL)-6) were recorded at baseline. During median follow-up of 38 months, 34 patients died, and 51 patients underwent renal transplantation. We analyzed spline curves showing sub-distribution hazard risk (sHR) for all-cause mortality with biological age calculated by SAF and chronological age by the Fine and Gray competing risk analysis. Results There was a significant association between biological age calculated by SAF and chronological age (rho=0.48; p Conclusion All-cause mortality risk increased linearly with higher chronological age and SAF-estimated biological age - and with similar magnitude of sHR for the two - suggesting that prediction of mortality risk based on SAF is not superior compared to chronological age in CKD. We conclude that biological age calculated by SAF and chronological age are equally robust predictors of clinical outcomes in CKD; however, both indices are influenced by the inflammatory status.

Background and Aims Ageing represents the greatest risk factor contributing to increased morbidity and mortality in most chronic diseases; it encompasses numerous biological changes resulting in declining physiological function and increasing burden of disease. Whether new biomarkers of ageing and risk scores for predicting physiological outcomes, including mortality, are applicable and more accurate than chronological age in patients with chronic kidney disease (CKD) is not clear. So far, the DNA methylation (DNAm) PhenoAge biomarker of ageing (Levine et al. Aging 2018) has not been tested in CKD. While we had no access to DNAm data, we applied the phenotypic age estimate proposed by Levine et al., which was included in their calculations of DNAm PhenoAge, and tested the relationship between estimated phenotypic age (ePhenoAge) and chronological age, respectively, with all-cause mortality in patients with CKD. Method In a cohort of 333 CKD patients (stage 1, n=78; stage 3-4, n=64; and stage 5, n=191) with median age 56 years, 43% females, 24% diabetes (DM), 25% cardiovascular disease (CVD), and 22% malnourished, we estimated age by ePhenoAge, using a formula with calculations based on nine biomarkers and chronological age, and compared this age index with chronological age. Framingham risk score, body composition, nutritional status, handgrip strength, and various biochemical markers (white blood cells, mean cell volume, hemoglobin, albumin, creatinine, glucose, calcium, alkaline phosphatase, intact-parathyroid hormone, triglyceride, cholesterol, HDL-cholesterol, high-sensitivity C-reactive protein (hsCRP), and interleukin (IL)-6) were recorded. During a median follow-up period of 52 months, 65 patients died, and 111 patients underwent renal transplantation. We used spline curve to illustrate sub-distribution hazard risk (sHR) for all-cause mortality versus increasing ePhenoAge and chronological age respectively as obtained by the Fine and Gray competing risk analysis. Results In univariate analyses, IL-6 (rho=0.49, p Conclusion All-cause mortality risk was associated with increasing chronological age in competing risk analysis with adjustments of confounders. A similar trend was observed for ePhenoAge, a finding which to a large extent may be explained by the inflammatory status of the study subjects. However, contrary to expectations, ePhenoAge was not as powerful as chronological age in predicting mortality, underlining that our knowledge about factors influencing phenotypic age in CKD patients is still limited. This should motivate further study of the potential role of other estimates of biological age in CKD.

Chocolate is a widely appreciated foodstuff with historical appreciation as a food from the gods. In addition to its highly palatable taste, it is a rich source of (poly)phenolics, which have several proposed salutogenic effects, including neuroprotective anti-inflammatory, anti-oxidant and cardioprotective capabilities. Despite the known benefits of this ancient foodstuff, there is a paucity of information on the effects of chocolate on in the context of chronic kidney disease (CKD). This review focusses on the potential salutogenic contribution of chocolate intake, to mitigate inflammatory and oxidative burden in CKD, its potential, for cardiovascular protection and on the maintenance of diversity in gut microbiota, as well as clinical perspectives, on regular chocolate intake by CKD patients.

International audience; Inflammatory and innate immune responses triggered by pathogen-associated and other danger-associated signals emerging during infections, results in the activation of cytosolic inflammasomes. The nod-like receptor pyrin domain containing 3 (NLRP3) is one of the inflammasomes mediating such responses through the activation of caspase-1, which increases the production and release of pro-inflammatory cytokines, such as IL-1β and IL-18 and induces programmed cell death through pyroptosis. NLRP3 is thought to play a crucial role in the underlying inflammatory responses in many lifestyles related chronic diseases. Consequently, research on the NLRP3 inflammasome has expanded dramatically in recent years. Although several studies have investigated the role of NLRP3 activation in chronic kidney disease (CKD), few studies have evaluated strategies to modulate its activation by means of interventions using non-pharmacological strategies. This review discusses some nutritional strategies (bioactive compounds, probiotics and caloric restriction) that have been shown to influence NLRP3 in experimental models of renal disease, and in CKD. It discusses how nutritional interventions could potentially dampen NLRP3 associated inflammatory burden, as part of nutritional strategies to prevent and treat CKD and its complications.

The underdeveloped opportunity to use the broad awareness of the diversity of animal life and comparative physiology (i.e. biomimetics) as nature´s own road map to provide novel insights and solutions from burden of lifestyle diseases has recently been discussed. Since human health, environmental changes and animal welfare are closely related (i.e. the 'one health' or 'planetary health' approach), such studies require close interdisciplinary collaboration including medical doctors, veterinarians, zoologists, climate researchers, ecologists, biologists and anthropologists. The ongoing coronavirus 2019 (COVID‐19) pandemic is a sobering example of the urgent need for global interdisciplinary collaboration, integrating human and animal health with environmental sustainability and ecosystem health. To begin with, it is worth noting that there is simply nothing uniquely Chinese about the COVID‐19 outbreak. The explanations for why so many epidemics seem to arise in China may not only be cultural, but also a matter of its current economic geography paired with the close interface between wildlife, livestock and humans. This is abundantly clear if we compare China to the United States, or Europe, when the latter were hubs of global production and mass industrial employment. The geography of blame, naming a germ after a country or ethnic group, has often been a symbol of helplessness during previous pandemics, detracting from the global aspect and unfairly labelling a country or ethnic group as being solely responsible. Ironically, the ‘Spanish flu’ pandemic of 1918 likely originated from a farm community in south‐western Kansas. Whilst previous pandemics were mainly linked to crises resulting from wars, the COVID‐19 pandemic is linked to a crisis based on environmental pollution, exploitation of the natural world, wildlife abuse and subsequent cumulative consequences on human health.

The WHO 2016 report indicates that worldwide obesity is rising, with over 600 million people in the obese range (BMI>30). The recommended daily calorie intake for adults is 2000 kcal and 2500 kcal for women and men respectively. The average American consumes 3770 kcal/day and the average person in the UK consumes 3400 kcal/day. With such increased caloric intake, there is an increased load on metabolic pathways, in particular glucose metabolism. Such metabolism requires micronutrients as enzyme co-factors. The recommended daily allowance (RDA) for thiamine is 1.3 mg/day and 0.5 mg thiamine is required to process 1000 kilocalories (kcal). Therefore, despite the appearance of being overfed, there is now increasing evidence that the obese population may nutritionally depleted of essential micronutrients. Thiamine deficiency has been reported to be in the region of 16-47% among patients undergoing bariatric surgery for obesity. Thiamine, in turn, requires magnesium to be in its active form thiamine diphosphate, (TDP). TDP also requires magnesium to achieve activation of TDP dependent enzymes, including transketolase (TK), pyruvate dehydrogenase (PDH) and alpha-keto glutaric acid dehydrogenase (AKGDH), during metabolism of glucose. Thiamine and magnesium therefore play a critical role in glucose metabolism and their deficiency may result in the accumulation of anaerobic metabolites including lactate due to a mismatch between caloric burden and function of thiamine dependent enzymes. It may therefore be postulated that thiamine and magnesium deficiency are under-recognized in obesity and may be important in the progress of obesity and obesity related chronic disease states. The aim of the present systematic review was to examine the role of thiamine dependent enzymes in obesity and obesity related chronic disease states.

Ramzi Lakhdar,1 Dagmara McGuinness,2 Ellen M Drost,1 Paul G Shiels,2 Ricardo Bastos,3 William MacNee,1,4 Roberto A Rabinovich1,4 1ELEGI Colt Laboratory, MRC Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK; 2Wolfson Wohl Translational Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; 3IDIBAPS, University of Barcelona, Barcelona, Spain; 4Respiratory Department, Royal Infirmary of Edinburgh, Edinburgh, UK Purpose: Skeletal muscle wasting is an independent predictor of health-related quality of life and survival in patients with COPD, but the complexity of molecular mechanisms associated with this process has not been fully elucidated. We aimed to determine whether an impaired ability to repair DNA damage contributes to muscle wasting and the accelerated aging phenotype in patients with COPD. Patients and methods: The levels of phosphorylated H2AX (γH2AX), a molecule that promotes DNA repair, were assessed in vastus lateralis biopsies from 10 COPD patients with low fat-free mass index (FFMI; COPDL), 10 with preserved FFMI and 10 age- and gender-matched healthy controls. A panel of selected markers for cellular aging processes (CDKN2A/p16ink4a, SIRT1, SIRT6, and telomere length) were also assessed. Markers of oxidative stress and cell damage and a panel of pro-inflammatory and anti-inflammatory cytokines were evaluated. Markers of muscle regeneration and apoptosis were also measured. Results: We observed a decrease in γH2AX expression in COPDL, which occurred in association with a tendency to increase in CDKN2A/p16ink4a, and a significant decrease in SIRT1 and SIRT6 protein levels. Cellular damage and muscle inflammatory markers were also increased in COPDL. Conclusion: These data are in keeping with an accelerated aging phenotype as a result of impaired DNA repair and dysregulation of cellular homeostasis in the muscle of COPDL. These data indicate cellular degeneration via stress-induced premature senescence and associated inflammatory responses abetted by the senescence-associated secretory phenotype and reflect an increased expression of markers of oxidative stress and inflammation. Keywords: COPD, skeletal muscle wasting, aging, inflammation, apoptosis

Many of the >2 million animal species that inhabit Earth have developed survival mechanisms that aid in the prevention of obesity, kidney disease, starvation, dehydration and vascular ageing; however, some animals remain susceptible to these complications. Domestic and captive wild felids, for example, show susceptibility to chronic kidney disease (CKD), potentially linked to the high protein intake of these animals. By contrast, naked mole rats are a model of longevity and are protected from extreme environmental conditions through mechanisms that provide resistance to oxidative stress. Biomimetic studies suggest that the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) offers protection in extreme environmental conditions and promotes longevity in the animal kingdom. Similarly, during months of fasting, immobilization and anuria, hibernating bears are protected from muscle wasting, azotaemia, thrombotic complications, organ damage and osteoporosis - features that are often associated with CKD. Improved understanding of the susceptibility and protective mechanisms of these animals and others could provide insights into novel strategies to prevent and treat several human diseases, such as CKD and ageing-associated complications. An integrated collaboration between nephrologists and experts from other fields, such as veterinarians, zoologists, biologists, anthropologists and ecologists, could introduce a novel approach for improving human health and help nephrologists to find novel treatment strategies for CKD.

Under normal physiological conditions, free radical generation and antioxidant defences are balanced, and reactive oxygen species (ROS) usually act as secondary messengers in a plethora of biological processes. However, when this balance is impaired, oxidative stress develops due to imbalanced redox homeostasis resulting in cellular damage. Oxidative stress is now recognized as a trigger of cellular senescence, which is associated with multiple chronic 'burden of lifestyle' diseases, including atherosclerosis, type-2 diabetes, chronic kidney disease and vascular calcification; all of which possess signs of early vascular ageing.\ud \ud Nuclear factor erythroid 2-related factor 2 (Nrf2), termed the master regulator of antioxidant responses, is a transcription factor found to be frequently dysregulated in conditions characterized by oxidative stress and inflammation. Recent evidence suggests that activation of Nrf2 may be beneficial in protecting against vascular senescence and calcification. Both natural and synthetic Nrf2 agonists have been introduced as promising drug classes in different phases of clinical trials. However, overexpression of the Nrf2 pathway has also been linked to tumorigenesis, which highlights the requirement for further understanding of pathways involving Nrf2 activity, especially in the context of cellular senescence and vascular calcification.\ud \ud Therefore, comprehensive translational pre-clinical and clinical studies addressing the targeting capabilities of Nrf2 agonists are urgently required. The present review discusses the impact of Nrf2 in senescence and calcification in early vascular ageing, with focus on the potential clinical implications of Nrf2 agonists and non-pharmacological Nrf2 therapeutics.

Objective: To explore putative different impacts of delayed graft function(DGF) on long-term graft survival in kidneys donated after brain death (DBD)and circulatory death (DCD).Background: Despite a 3-fold higher incidence of DGF in DCD grafts, largestudies show equivalent long-term graft survival for DBD and DCD grafts.This observation implies a differential impact of DGF on DBD and DCD graftsurvival. The contrasting impact is remarkable and yet unexplained.Methods: The impact of DGF on DBD and DCD graft survival was evaluatedin 6635 kidney transplants performed in The Netherlands. DGF severity andfunctional recovery dynamics were assessed for 599 kidney transplantsperformed at the Leiden Transplant Center. Immunohistochemical staining,gene expression profiling, and Ingenuity Pathway Analysis were used toidentify differentially activated pathways in DBD and DCD grafts.Results: While DGF severely impacted 10-year graft survival in DBD grafts(HR 1.67; P < 0.001), DGF did not impact graft survival in DCD grafts (HR1.08; P ¼ 0.63). Shorter dialysis periods and superior posttransplant eGFRs inDBD grafts show that the differential impact was not caused by a more severeDGF phenotype in DBD grafts. Immunohistochemical evaluation indicatesthat pathways associated with tissue resilience are present in kidney grafts.Molecular evaluation showed selective activation of resilience-associatedpathways in DCD grafts.Conclusions: This study shows an absent impact of DGF on long-term graftsurvival in DCD kidneys. Molecular evaluation suggests that the differentialimpact of DGF between DBD and DCD grafts relates to donor-type specificactivation of resilience pathways in DCD grafts.

Ageing is a process of decline in physiological function and capability over time. It is an anticipated major burden on societal health-care costs due to an increasingly aged global population. Accelerated biological ageing is a feature of age-related morbidities, which also appear to share common underpinning features, including low-grade persistent inflammation, phosphate toxicity, diminished Nrf2 activity, a depleted metabolic capability, depressed mitochondrial biogenesis and a low diversity gut microbiome. Social, psychological, lifestyle and nutritional risk factors can all influence the trajectory of age-related health, as part of an individual's exposome, which reflects the interplay between the genome and the environment. This is manifest as allostatic (over)load reflecting the burden of lifestyle/disease at both a physiological and molecular level. In particular, age-related genomic methylation levels and inflammatory status reflect exposome differences. These features may be mediated by changes in microbial diversity. This can drive the generation of pro-inflammatory factors, such as TMAO, implicated in the ‘diseasome’ of ageing. Additionally, it can be influenced by the ‘foodome’, via nutritional differences affecting the availability of methyl donors required for maintenance of the epigenome and by the provision of nutritionally derived Nrf2 agonists. Both these factors influence age-related physiological resilience and health. This offers novel insights into possible interventions to improve health span, including a rage of emerging senotherapies and simple modifications of the nutritional and environmental exposome. In essence, the emerging strategy is to treat ageing processes common to the diseasome of ageing itself and thus preempt the development or progression of a range of age-related morbidities.

Background: \ud There is a substantial gap in health and longevity between more affluent and more deprived areas, and more knowledge of the determinants of this health divide is required. Experience of the local residential environment is important for health although few studies have examined this in relation to biological markers of age such as telomere length. We sought to examine if residents’ perceptions of neighbourhood stressors over time were associated with telomere length in a community study.\ud \ud Methodology/Principal findings: \ud In a prospective cohort study of 2186 adults in the West of Scotland, we measured neighbourhood stressors at three time points over a 12-year period and telomere length at the end of the study. Using linear regression models, we found that a higher accumulation of neighbourhood stressors over time was associated with shorter telomere length, even after taking cohort, social class, health behaviours (smoking status, diet, physical activity), BMI and depression into account among females only (Beta = 0.007; 95%CI [0.001, 0.012]; P

Objectives:\ud \ud There has been considerable change in the practice of deceased kidney transplantation in the past 15 years, with more extreme phenotypes implanted. The aim of this study was to determine whether increased use of expanded criteria donors (extended criteria donors and donors after circulatory death) affected clinical outcomes, including the incidence and pattern of delayed graft function.\ud Methods and materials:\ud \ud A retrospective analysis of 1359 renal transplants was performed over 15 years. The first 10 years of data (group 1) were compared with the subsequent 5 years (group 2). Outcomes were analyzed at 6 months and 12 months in addition to serum creatinine and patterns of delayed graft function (posttransplant times: on hemodialysis, to peak creatinine, for creatinine to half, and for creatinine to fall within 10% of baseline).\ud Results:\ud \ud There was a significant increase in the percentage of expanded criteria donor allografts used in group 2 with a significant increase in the incidence of delayed graft function. Despite this, serum creatinine and the incidence of biopsy-proven acute rejection had both improved in group 2. Group 2 expanded criteria donor kidneys had a significantly lower incidence of type 1 delayed graft function and a significantly higher incidence of types 3 and 4 delayed graft function. Time for creatinine to half in both groups was the best predictor of a serum creatinine

A more comprehensive understanding of the human ageing process is required to help mitigate the increasing burden of age-related morbidities in a rapidly growing global demographic of elderly individuals. One exciting novel strategy that has emerged to intervene involves the use of extracellular vesicles to engender tissue regeneration. Specifically, this employs their molecular payloads to confer changes in the epigenetic landscape of ageing cells and ameliorate the loss of functional capacity. Understanding the biology of extracellular vesicles and the specific roles they play during normative ageing will allow for the development of novel cell-free therapeutic interventions. Hence, the purpose of this review is to summarise the current understanding of the mechanisms that drive ageing, critically explore how extracellular vesicles affect ageing processes and discuss their therapeutic potential to mitigate the effects of age-associated morbidities and improve the human health span.

Background: \ud Both active smoking and second-hand smoke (SHS) are important risk factors for many age-related diseases. Active smoking is associated with shortened telomere length. However, whether SHS accelerates telomere attrition with age is uncertain. The aim of this study was to examine the association between SHS exposure and shortening by age of leukocyte telomere length among adult non-smokers.\ud Methods: \ud We undertook a cross-sectional study of the association between self-reported levels of SHS exposure and telomere length shortening per annum on a subgroup of participants from the Scottish Family Health Study. Inclusion was restricted to non-smokers aged ≥ 18 years, who had provided self-reported overall usual SHS exposure (total hours per week) and blood samples for telomere analysis. Linear regression models were used to compare the ratio of telomere repeat copy number to single copy gene number (T/S)by age according to SHS exposure.\ud Results: \ud Of the 1303 eligible participants, 779 (59.8%) reported no SHS exposure, 495 (38.0%) low exposure (1–19 h per week) and 29 (2.2%) high exposure (≥20 h per week). In the univariate linear regression analyses, relative T/S ratio declined with increasing age in all exposure groups. Telomere length decreased more rapidly with increasing age among those with high exposure to SHS [adjusted coefficient −0.019, 95% confidence interval (CI) −0.031- −0.007) when compared with both those with no exposure to SHS (adjusted coefficient −0.006, 95% CI −0.008- −0.004) (high vs no SHS: P = 0.010) and those with low exposure to SHS (adjusted coefficient −0.005, 95% CI −0.007- −0.003) (high vs low SHS: P = 0.005).\ud Conclusions: \ud Our findings suggest that high SHS exposure may accelerate normal biological ageing, and support efforts to protect the public from SHS exposure. Further studies on relevant mechanisms should be conducted.

Aims: To analyze changes in telomere length (TL) after dialysis initiation. Methods: In 59 Japanese incident dialysis patients, associations between TL in peripheral blood leukocytes, inflammatory biomarkers and nutritional status at baseline and changes in TL during 1 year of dialysis, were investigated. Results: Whereas relative TL decreased by 8.6% (median 14.4%), TL elongation occurred in 16 patients (27%). Change in TL (ΔTL), defined as TL at 1 year minus TL at baseline, was associated with baseline TL (ρ = -0.70, p < 0.0001) and leukocyte count (ρ = 0.26, p = 0.044). In a logistic regression model, baseline TL (p < 0.0001) and leukocyte count (p = 0.047) were associated with ΔTL. Conclusions: TL shortening was observed in most incident dialysis patients. In 16 of the 59 patients, TL elongation occurred, possibly reflecting a more robust biological aging in patients whose naïve leukocytes may have undergone less proliferation to replace lost leukocytes.

Aim and background: Chronic inflammation associates with increased senescence, which is a strong predictor for cardiovascular disease. We hypothesised that inflammation accelerates senescence and thereby enhances the risk of cardiovascular disease in gout. Methods: We assessed replicative senescence by quantifying telomere length (TL) in a discovery cohort of 145 Dutch patients with gout and 273 healthy individuals and validated our results in 474 patients with gout and 293 healthy participants from New Zealand. Subsequently, we investigated the effect of cardiovascular disease on TL of all participants. Also, we measured TL of CD4+ and CD8+ T lymphocytes, B lymphocytes, monocytes, natural killer cells and plasmacytoid dendritic cells. Additionally, we assessed the potential temporal difference in TL and telomerase activity. Results: TL in PBMCs of healthy donors decreased over time, reflecting normal ageing. Patients with gout demonstrated shorter telomeres (p=0.001, R2=0.01873). In fact, the extent of telomere erosion in patients with gout was higher at any age compared with healthy counterparts at any age (p

Background: Telomere length is a putative biomarker of ageing, morbidity and mortality. Its application is hampered by lack of widely applicable reference ranges and uncertainty regarding the present limits of measurement reproducibility within and between laboratories.\ud \ud Methods: We instigated an international collaborative study of telomere length assessment: 10 different laboratories, employing 3 different techniques [Southern blotting, single telomere length analysis (STELA) and real-time quantitative PCR (qPCR)] performed two rounds of fully blinded measurements on 10 human DNA samples per round to enable unbiased assessment of intra- and inter-batch variation between laboratories and techniques.\ud \ud Results: Absolute results from different laboratories differed widely and could thus not be compared directly, but rankings of relative telomere lengths were highly correlated (correlation coefficients of 0.63–0.99). Intra-technique correlations were similar for Southern blotting and qPCR and were stronger than inter-technique ones. However, inter-laboratory coefficients of variation (CVs) averaged about 10% for Southern blotting and STELA and more than 20% for qPCR. This difference was compensated for by a higher dynamic range for the qPCR method as shown by equal variance after z-scoring. Technical variation per laboratory, measured as median of intra- and inter-batch CVs, ranged from 1.4% to 9.5%, with differences between laboratories only marginally significant (P = 0.06). Gel-based and PCR-based techniques were not different in accuracy.\ud \ud Conclusions: Intra- and inter-laboratory technical variation severely limits the usefulness of data pooling and excludes sharing of reference ranges between laboratories. We propose to establish a common set of physical telomere length standards to improve comparability of telomere length estimates between laboratories.

Introduction Cardio-metabolic risk factors have been associated with poor physical and mental health. Epidemiological studies have shown peripheral risk markers to be associated with poor cognitive functioning in normal healthy population and in disease. The aim of the study was to explore the relationship between cardio-metabolic risk factors and cortical thickness in a neurologically healthy middle aged population-based sample. Methods T1-weighted MRI was used to create models of the cortex for calculation of regional cortical thickness in 40 adult males (average age = 50.96 years), selected from the pSoBid study. The relationship between cardio-vascular risk markers and cortical thickness across the whole brain, was examined using the general linear model. The relationship with various covariates of interest was explored. Results Lipid fractions with greater triglyceride content (TAG, VLDL and LDL) were associated with greater cortical thickness pertaining to a number of regions in the brain. Greater C reactive protein (CRP) and intercellular adhesion molecule (ICAM-1) levels were associated with cortical thinning pertaining to perisylvian regions in the left hemisphere. Smoking status and education status were significant covariates in the model. Conclusions This exploratory study adds to a small body of existing literature increasingly showing a relationship between cardio-metabolic risk markers and regional cortical thickness involving a number of regions in the brain in a neurologically normal middle aged sample. A focused investigation of factors determining the inter-individual variations in regional cortical thickness in the adult brain could provide further clarity in our understanding of the relationship between cardio-metabolic factors and cortical structures., Highlights • The relationship between coronary risk factors and cortical thickness is unclear. • We examine this relationship in neurologically healthy middle aged adults. • Greater lipid fractions were associated with greater regional cortical thickness. • Greater CRP and ICAM-1 were associated with regional cortical thinning.

ObjectiveTo evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby methyl-CpG-binding protein 2 gene (MECP2).MethodsWe analysed a total of 3065 women with SSc and 2630 unaffected controls from five independent Caucasian cohorts. Four tag single-nucleotide polymorphisms of MECP2 (rs3027935, rs17435, rs5987201 and rs5945175) and the IRAK1 variant rs1059702 were genotyped using TaqMan predesigned assays. A meta-analysis including all cohorts was performed to test the overall effect of these Xq28 polymorphisms on SSc.ResultsIRAK1 rs1059702 and MECP2 rs17435 were associated specifically with diffuse cutaneous SSc (PFDR=4.12×10−3, OR=1.27, 95% CI 1.09 to 1.47, and PFDR=5.26×10−4, OR=1.30, 95% CI 1.14 to 1.48, respectively), but conditional logistic regression analysis showed that the association of IRAK1 rs1059702 with this subtype was explained by that of MECP2 rs17435. On the other hand, IRAK1 rs1059702 was consistently associated with presence of pulmonary fibrosis (PF), because statistical significance was observed when comparing SSc patients PF+ versus controls (PFDR=0.039, OR=1.30, 95% CI 1.07 to 1.58) and SSc patients PF+ versus SSc patients PF− (p=0.025, OR=1.26, 95% CI 1.03 to 1.55).ConclusionsOur data clearly suggest the existence of two independent signals within the Xq28 region, one located in IRAK1 related to PF and another in MECP2 related to diffuse cutaneous SSc, indicating that both genes may have an impact on the clinical outcome of the disease.

Pathfinder cells (PCs) are a novel class of adult-derived cells that facilitate functional repair of host tissue. We used rat PCs to demonstrate that they enable the functional mitigation of ischemia reperfusion (I/R) injury in a mouse model of renal damage. Female C57BL/6 mice were subjected to 30 min of renal ischemia and treated with intravenous (i.v.) injection of saline (control) or male rat pancreas-derived PCs in blinded experimentation. Kidney function was assessed 14 days after treatment by measuring serum creatinine (SC) levels. Kidney tissue was assessed by immunohistochemistry (IHC) for markers of cellular damage, proliferation, and senescence (TUNEL, Ki67, p16ink4a, p21). Fluorescence in situ hybridization (FISH) was performed to determine the presence of any rat (i.e., pathfinder) cells in the mouse tissue. PC-treated animals demonstrated superior renal function at day 14 post-I/R, in comparison to saline-treated controls, as measured by SC levels (0.13 mg/dL vs. 0.23 mg/dL, p

Delayed graft function (DGF) is a major issue in kidney transplantation and is associated with reduced graft and patient survival. The condition results from the summative effects of multiple injurious processes associated with transplantation with many underlying factors being nonmodifiable. Reducing cold ischemic time and machine perfusion have decreased the DGF incidence but peri-/postoperative injury resulting from suboptimal perfusion may also be critical to the development of DGF. We investigated the effect of perfusion parameters and other key variables on the incidence of DGF in 149 consecutive renal transplants. The occurrence of any recorded subtarget (70 mm Hg) mean arterial pressure (MAP) was significantly associated with DGF (perioperative P = .005; postoperative P = .002) while the occurrence of a subtarget (8 cm H(2)O) central venous pressure (CVP) among other variables was not. Routine continuous blood pressure monitoring is rare postoperatively and is shown to be more accurate than CVP in assessing renal perfusion and guiding management in the postoperative period.

It has been hypothesized that one way in which lower socioeconomic status (SES) affects health is by increasing the rate of biological aging. A widely used marker of biological aging is telomere length. Telomeres are structures at the ends of chromosomes that erode with increasing cell proliferation and genetic damage. We aimed to identify, through systematic review and meta-analysis, whether lower SES (greater deprivation) is associated with shorter telomeres. Thirty-one articles, including 29 study populations, were identified. We conducted 3 meta-analyses to compare the telomere lengths of persons of high and low SES with regard to contemporaneous SES (12 study populations from 10 individual articles), education (15 study populations from 14 articles), and childhood SES (2 study populations from 2 articles). For education, there was a significant difference in telomere length between persons of high and low SES in a random-effects model (standardized mean difference (SMD) = 0.060, 95% confidence interval (CI): 0.002, 0.118; P = 0.042), although a range of sensitivity analyses weakened this association. There was no evidence for an association between telomere length and contemporaneous SES (SMD = 0.104, 95% CI: -0.027, 0.236; P = 0.119) or childhood SES (SMD = -0.037, 95% CI: -0.143, 0.069; P = 0.491). These results suggest weak evidence for an association between SES (as measured by education) and biological aging (as measured by telomere length), although there was a lack of consistent findings across the SES measures investigated here.

Renal ischemia reperfusion injury (IRI) is a major problem, currently without treatments in clinical use. This reflects the failure of animal models to mimic the severity of IRI observed in clinical practice. Most described models lack both the ability to inflict a permanent reduction in renal function and the sensitivity to demonstrate the protective efficacy of different therapies in vivo. To test novel cell-based therapies, we have developed a model of renal IRI in Fisher 344 rats. Animals were subjected to 120 min of unilateral warm ischemia, during which they underwent an intra-renal artery infusion of therapeutic agents or vehicle. At either 2 or 6 weeks post-surgery, animals underwent terminal glomerular filtration rate (GFR) studies by inulin clearance to most accurately quantify renal function. Harvested kidneys underwent histological analysis. Compared to sham operations, saline treated animals suffered a long-term reduction in GFR of ≈50%. Histology revealed short- and long-term disruption of renal architecture. Despite the injury severity, post-operative animal losses are

The association of the circulating serum vitamin D metabolite 25-hydroxyvitamin D (25OHD) with atherosclerotic burden is unclear, with previous studies reporting disparate results.Psychological, social and biological determinants of ill health (pSoBid) is a study of participants aged 35-64 years from Glasgow who live at extremes of the socioeconomic spectrum. Vitamin D deficiency was defined as 25OHD 25nmol/L, as per convention. Cross-sectional associations between circulating 25OHD concentrations and a range of socioeconomic, lifestyle, and biochemistry factors, as well as carotid intima media thickness (cIMT) and plaque presence were assessed in 625 participants.Geometric mean levels of circulating 25OHD were higher among the least deprived (45.6 nmol/L, 1-SD range 24.4-85.5) versus most deprived (34.2 nmol/L, 1-SD range 16.9-69.2; p 0.0001). In the least deprived group 15% were "deficient" in circulating 25OHD versus 30.8% in the most deprived (χ(2)p 0.0001). Log 25OHD was 27% lower among smokers (p 0.0001), 20% higher among the physically active versus inactive (p = 0.01), 2% lower per 1 kg/m(2) increase in body mass index (BMI) (p 0.0001), and showed expected seasonal variation (χ(2)p 0.0001). Log 25OHD was 13% lower in the most versus least deprived independent of the aforementioned lifestyle confounding factors (p = 0.03). One unit increase in log 25OHD was not associated with atherosclerotic burden in univariable models; cIMT (effect estimate 0.000 mm [95% CI -0.011, 0.012]); plaque presence (OR 0.88 [0.75, 1.03]), or in multivariable models.There is no strong association of 25OHD with cIMT or plaque presence, despite strong evidence 25OHD associates with lifestyle factors and socioeconomic deprivation.

Reproducibility of telomere length assessment : Authors' Response to Damjan Krstajic and Ljubomir Buturovic

PURPOSE OF REVIEW: There is increasing clinical and pathophysiological evidence that a premature aging process is involved in the pathogenesis of systemic complications of many chronic organ diseases, which result in analogous phenotypes, including premature vascular aging, osteoporosis and muscle wasting. Novel developments from research into the aging process will, therefore, have relevance for understanding complications of organ diseases, such as chronic kidney disease and chronic obstructive pulmonary disease. The aim of the present article is to combine recent literature on aging mechanisms with evidence on the pathogenesis of systemic complications of these two chronic debilitating disorders. RECENT FINDINGS: Recently, nine hallmarks of aging have been identified. In this review, we argue that all of these hallmarks are relevant for the pathogenesis of premature aging processes in chronic obstructive pulmonary disease and chronic kidney disease. Additionally, organ-specific alterations in proaging mechanisms, which reveal differences in phenotype against a generic background of premature aging, will be addressed. However, within patient populations who share a common diagnosis, clusters of patients with different phenotypes may be identified, which may show overlap with patients with other chronic diseases. SUMMARY: An increased understanding of the premature aging process as well as its systemic consequences may pave the way for 'precision' intervention as well as shared treatment opportunities between chronic debilitating diseases of various causes.

The number of aged individuals within the global population is increasing, which foreshadows a major societal and global health challenge. By 2050 those over 65 years old will outnumber children under 15 years of age. This situation will bring with it multifarious variations in health and functional status, occurring with increasing age and which remain incompletely understood. Ageing, however, is not solely a passive degenerative process but one that is actively regulated by distinct molecular pathways. Understanding this molecular basis of ageing is an essential step for therapeutic manipulation to combat age-related disease. Diseases such as SSc, RA and SLE may share common age related pathways of early dysregulation with other diseases of ageing, such that the biomarkers and interventions applied to prevent late stage disease will also tackle common fundamental pathways of ageing processes. This chapter will seek to explore and discuss the possible influence of these factors and their impact on disease processes, with specific reference to SSc in the context of it being a disease of ageing. It will address the contribution of socioeconomic, psychosocial and nutritional confounders of health span through the life course. In particular, it will seek to contextualize the development of inflammatory burden and allostatic overload and their contribution to morbidity and mortality. Importantly, this chapter will provide a context for transgenerational and other epigenetic effects, which are emerging as contributory components in disease susceptibility and progression.

The author name Batty DG should read Batty GD. The authors would like to apologise for any inconvenience caused.