Metabolic View on Human Healthspan: A Lipidome-Wide Association Study.

As ageing is a major risk factor for the development of non-communicable diseases, extending healthspan has become a medical and societal necessity. Precise lipid phenotyping that captures metabolic individuality could support healthspan extension strategies. This study applied 'omic-scale lipid profiling to characterise sex-specific age-related differences in the serum lipidome composition of healthy humans. A subset of the COmPLETE-Health study, composed of 73 young (25.2 ± 2.6 years, 43% female) and 77 aged (73.5 ± 2.3 years, 48% female) clinically healthy individuals, was investigated, using an untargeted liquid chromatography high-resolution mass spectrometry approach. Compared to their younger counterparts, aged females and males exhibited significant higher levels in 138 and 107 lipid species representing 15 and 13 distinct subclasses, respectively. Percentage of difference ranged from 5.8% to 61.7% (females) and from 5.3% to 46.0% (males), with sphingolipid and glycerophophospholipid species displaying the greatest amplitudes. Remarkably, specific sphingolipid and glycerophospholipid species, previously described as cardiometabolically favourable, were found elevated in aged individuals. Furthermore, specific ether-glycerophospholipid and lyso-glycerophosphocholine species displayed higher levels in aged females only, revealing a more favourable lipidome evolution in females. Altogether, age determined the circulating lipidome composition, while lipid species analysis revealed additional findings that were not observed at the subclass level

Investigating the circulating sphingolipidome response to a single high-intensity interval training session within healthy females and males in their twenties (SphingoHIIT): Protocol for a randomised controlled trial.

Introduction: Growing scientific evidence indicates that sphingolipids predict cardiometabolic risk, independently of and beyond traditional biomarkers such as low-density lipoprotein cholesterol. To date, it remains largely unknown if and how exercise, a simple, low-cost, and patient-empowering modality to optimise cardiometabolic health, influences sphingolipid levels. The SphingoHIIT study aims to assess the response of circulating sphingolipid species to a single session of high-intensity interval training (HIIT). Methods: This single-centre randomised controlled trial (RCT) will last 11 days per participant and aim to include 32 young and healthy individuals aged 20-29 (50% females). Participants will be randomly allocated to the HIIT (n= 16) or control groups (physical rest, n= 16). Participants will self-sample fasted dried blood spots for three consecutive days before the intervention (HIIT versus rest) to determine baseline sphingolipid levels. Dried blood spots will also be collected at five time points (2, 15, 30, 60min, and 24h) following the intervention (HIIT versus rest). To minimise the dietary influence, participants will receive a standardised diet for four days, starting 24 hours before the first dried blood sampling. For females, interventions will be timed to fall within the early follicular phase to minimise the menstrual cycle's influence on sphingolipid levels. Finally, physical activity will be monitored for the whole study duration using a wrist accelerometer. Ethics and dissemination: The Ethics Committee of Northwest and Central Switzerland approved this protocol (ID 2022-00513). Findings will be disseminated in scientific journals and meetings. Trial Registration The trial was registered on www.clinicaltrials.gov (NCT05390866, https://clinicaltrials.gov/ct2/show/NCT05390866) on May 25, 2022

Coupling Stable Isotope Analysis with Gas Push-Pull Tests to Derive In Situ Values for the Fractionation Factor αox Associated with the Microbial Oxidation of Methane in Soils

A prerequisite for the application of stable isotope fractionation for the quantification of the methane (CH4) oxidation efficiency of landfill covers is that the fractionation factor αox is known or can be estimated with adequate accuracy. So far, αox has only been determined in laboratory experiments. In this study, αox was determined under in situ conditions in the field by coupling two independent methods, gas push-pull tests and stable isotope analysis, to assess biological fractionation of CH4 isotopologues in landfill cover soils. On six landfills with nine points of investigation, 22 measurements were performed, covering a wide range of environmental conditions, such as soil temperature and moisture and observed oxidation rates. Values for αox varied between near 1, indicating little fractionation, and 1.151. Correlation of αox with the CH4 oxidation rate found by gas push-pull tests revealed a clear asymptotic relationship, with low rates being associated with high values for αox and high rates resulting in little fractionation. Values for αox varied between the different landfills and between the individual points of investigation on the same landfill. The latter is assumed to reflect the spatial variability of methanotrophic activity due to spatial variability in soil moisture and hence air-filled porosity as well as the spatial variability of gas fluxes. Significant variation of αox was observed for the same sampling point, presumably reflecting the temporal variability of factors influencing methanotrophic activity. These effects could include seasonally changing environmental conditions (e.g., soil temperature and moisture) but also the temporal variability of gas fluxes through the landfill soil cover, changing exposure of methanotrophs to CH4 and oxygen and hence their activity. The quantification of the CH4 oxidation efficiency using fractionation of stable isotopes is very sensitive to αox. Assuming a value constant in time and space and transferring this value from laboratory experiments to field settings entails significant uncertainty regarding the quantification of CH4 oxidation.Geo-engineerin

How Ceramides Orchestrate Cardiometabolic Health-An Ode to Physically Active Living.

Cardiometabolic diseases (CMD) represent a growing socioeconomic burden and concern for healthcare systems worldwide. Improving patients' metabolic phenotyping in clinical practice will enable clinicians to better tailor prevention and treatment strategy to individual needs. Recently, elevated levels of specific lipid species, known as ceramides, were shown to predict cardiometabolic outcomes beyond traditional biomarkers such as cholesterol. Preliminary data showed that physical activity, a potent, low-cost, and patient-empowering means to reduce CMD-related burden, influences ceramide levels. While a single bout of physical exercise increases circulating and muscular ceramide levels, regular exercise reduces ceramide content. Additionally, several ceramide species have been reported to be negatively associated with cardiorespiratory fitness, which is a potent health marker reflecting training level. Thus, regular exercise could optimize cardiometabolic health, partly by reversing altered ceramide profiles. This short review provides an overview of ceramide metabolism and its role in cardiometabolic health and diseases, before presenting the effects of exercise on ceramides in humans

The metabolic signature of cardiorespiratory fitness: a protocol for a systematic review and meta-analysis.

A low cardiorespiratory fitness (CRF) is a strong and independent predictor of cardiometabolic, cancer and all-cause mortality. To date, the mechanisms linking CRF with reduced mortality remain largely unknown. Metabolomics, which is a powerful metabolic phenotyping technology to unravel molecular mechanisms underlying complex phenotypes, could elucidate how CRF fosters human health. This study aims at systematically reviewing and meta-analysing the literature on metabolites of any human tissue sample, which are positively or negatively associated with CRF. Studies reporting estimated CRF will not be considered. No restrictions will be placed on the metabolomics technology used to measure metabolites. PubMed, Web of Science and EMBASE will be searched for relevant articles published until the date of the last search. Two authors will independently screen full texts of selected abstracts. References and citing articles of included articles will be screened for additional relevant publications. Data regarding study population, tissue samples, analytical technique, quality control, data processing, metabolites associated to CRF, cardiopulmonary exercise test protocol and exercise exhaustion criteria will be extracted. Methodological quality will be assessed using a modified version of QUADOMICS. Narrative synthesis as well as tabular/charted presentation of the extracted data will be included. If feasible, meta-analyses will be used to investigate the associations between identified metabolites and CRF. Potential sources of heterogeneity will be explored in meta-regressions. No ethics approval is required. The results will be published in a peer-reviewed journal and as conference presentation. CRD42020214375

The Metabolic Signature of Cardiorespiratory Fitness: A Systematic Review.

Cardiorespiratory fitness (CRF) is a potent health marker, the improvement of which is associated with a reduced incidence of non-communicable diseases and all-cause mortality. Identifying metabolic signatures associated with CRF could reveal how CRF fosters human health and lead to the development of novel health-monitoring strategies. This article systematically reviewed reported associations between CRF and metabolites measured in human tissues and body fluids. PubMed, EMBASE, and Web of Science were searched from database inception to 3 June, 2021. Metabolomics studies reporting metabolites associated with CRF, measured by means of cardiopulmonary exercise test, were deemed eligible. Backward and forward citation tracking on eligible records were used to complement the results of database searching. Risk of bias at the study level was assessed using QUADOMICS. Twenty-two studies were included and 667 metabolites, measured in plasma (n = 619), serum (n = 18), skeletal muscle (n = 16), urine (n = 11), or sweat (n = 3), were identified. Lipids were the metabolites most commonly positively (n = 174) and negatively (n = 274) associated with CRF. Specific circulating glycerophospholipids (n = 85) and cholesterol esters (n = 17) were positively associated with CRF, while circulating glycerolipids (n = 152), glycerophospholipids (n = 42), acylcarnitines (n = 14), and ceramides (n = 12) were negatively associated with CRF. Interestingly, muscle acylcarnitines were positively correlated with CRF (n = 15). Cardiorespiratory fitness was associated with circulating and muscle lipidome composition. Causality of the revealed associations at the molecular species level remains to be investigated further. Finally, included studies were heterogeneous in terms of participants' characteristics and analytical and statistical approaches. CRD42020214375

Metabolic Impairment in Coronary Artery Disease: Elevated Serum Acylcarnitines Under the Spotlights.

Coronary artery disease (CAD) remains the leading cause of death worldwide. Expanding patients' metabolic phenotyping beyond clinical chemistry investigations could lead to earlier recognition of disease onset and better prevention strategies. Additionally, metabolic phenotyping, at the molecular species level, contributes to unravel the roles of metabolites in disease development. In this cross-sectional study, we investigated clinically healthy individuals (n = 116, 65% male, 70.8 ± 8.7 years) and patients with CAD (n = 54, 91% male, 67.0 ± 11.5 years) of the COmPLETE study. We applied a high-coverage quantitative liquid chromatography-mass spectrometry approach to acquire a comprehensive profile of serum acylcarnitines, free carnitine and branched-chain amino acids (BCAAs), as markers of mitochondrial health and energy homeostasis. Multivariable linear regression analyses, adjusted for confounders, were conducted to assess associations between metabolites and CAD phenotype. In total, 20 short-, medium- and long-chain acylcarnitine species, along with L-carnitine, valine and isoleucine were found to be significantly (adjusted p ≤ 0.05) and positively associated with CAD. For 17 acylcarnitine species, associations became stronger as the number of affected coronary arteries increased. This implies that circulating acylcarnitine levels reflect CAD severity and might play a role in future patients' stratification strategies. Altogether, CAD is characterized by elevated serum acylcarnitine and BCAA levels, which indicates mitochondrial imbalance between fatty acid and glucose oxidation

Physical activity and markers of glycation in older individuals: data from a combined cross-sectional and randomized controlled trial (EXAMIN AGE)

Advanced glycation end products (AGEs) are protein modifications that are predominantly formed from dicarbonyl compounds that arise from glucose and lipid metabolism. AGEs and sedentary behavior have been identified as a driver of accelerated (vascular) aging. The effect of physical activity on AGE accumulation is unknown. Therefore, we investigated whether plasma AGEs and dicarbonyl levels are different across older individuals that were active or sedentary and whether plasma AGEs are affected by high-intensity interval training (HIIT).; We included healthy older active (HA, n=38, 44.7% female, 60.1 ± 7.7 years old) and healthy older sedentary (HS, n=36, 72.2% female, 60.0 ± 7.3 years old) individuals as well as older sedentary individuals with increased cardiovascular risk (SR, n=84, 50% female, 58.7 ± 6.6 years old). The SR group was randomized into a 12-week walking-based HIIT program or control group. We measured protein-bound and free plasma AGEs and dicarbonyls by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) at baseline and after the HIIT intervention.; Protein-bound AGE Nε-(carboxymethyl)lysine (CML) was lower in SR (2.6 ± 0.5 μmol/l) and HS (3.1 ± 0.5 μmol/l) than in HA (3.6 ± 0.6 μmol/l; P<0.05) and remained significantly lower after adjustment for several potential confounders. None of the other glycation markers were different between HS and HA. HIIT did not change plasma AGEs and dicarbonyls in SR.; Although lifestyle interventions may act as important modulators of cardiovascular risk, HIIT is not a potent short-term intervention to reduce glycation in older individuals, underlining the need for other approaches, such as pharmacological agents, to reduce AGEs and lower cardiovascular risk in this population