Le tissu adipeux brun est spécialisé dans la dissipation de l’énergie sous forme de chaleur, par le processus de thermogénèse de non-frisson. De nombreuses études chez les rongeurs ont montré le rôle majeur du tissu adipeux brun ainsi que celui du tissu adipeux beige – présentant des similitudes dans les propriétés métaboliques et sécrétoires mais également des différences qui restent encore à être mieux définies – dans la thermorégulation et dans le maintien de la balance énergétique. Chez l’homme, les tissus adipeux brun/beige sont très présents chez le nouveau-né, déclinent avec l’âge, et sont positivement associés à la santé cardiovasculaire et métabolique. Cependant, l’impact de ces tissus sur le métabolisme chez l’adulte est très controversé. Parallèlement à un potentiel rôle dans le maintien de l’homéostasie énergétique à l’échelle de l’organisme entier, ces tissus pourraient exercer des effets locaux par la création de microenvironnements spécifiques contribuant au bon fonctionnement d’organes présents à leur proximité. Dans cette revue, nous faisons le point sur la biologie de ces tissus aux capacités oxydatives remarquables, sur les méthodes de détection et sur les résultats d’études cliniques rétrospectives et prospectives étudiant leur rôle dans la santé humaine.

Bone marrow adipocytes (BMAds) are a major component of the bone marrow (BM) that regulate bone turnover and hematopoiesis. In rodents, two distinct adipocyte populations exist: constitutive BMAds (cBMAds), located in areas devoid of hematopoietic cells and resistant to metabolic cues, and regulatory BMAds (rBMAds), interspersed within hematopoietic niches and responsive to energy stress. Despite their potential importance, rBMAds have remained poorly characterized due to their scarcity in rodents. Here, we used a high-yield method to isolate human rBMAds, enabling structural, proteomic, lipidomic, and functional analyses. Remarkably, human rBMAds are anucleate yet retain organelles and maintain lipid and glucose metabolism, but unlike their rodent counterparts, they lack lipolytic activity. They actively secrete factors that support hematopoiesis in vitro, implicating them as functional contributors to the BM niche. Collectively, these findings redefine key aspects of BMAds diversity in humans.

Brown adipose tissue is specialized in energy dissipation in the form of heat through the process of non-shivering thermogenesis. Numerous studies in rodents have demonstrated the major role of brown adipose tissue, as well as that of beige adipose tissue - which has similar metabolic and secretory properties but also differences that remain to be better defined - in thermoregulation and energy balance. In humans, brown/beige adipose tissues are very present in newborns, decline with age, and are positively associated with cardiovascular and metabolic health. However, the real impact of these tissues on human metabolism in adults remains highly controversial. In addition to their potential role in maintaining energy homeostasis at the whole organism level, these tissues may exert local effects by creating specific microenvironments that contribute to the proper functioning of tissues and organs present in their close proximity. In this review, we describe the biology of these tissues exhibiting remarkable oxidative capacities, the methods enabling their detection, and retrospective and prospective clinical studies investigating their role in human health. (c) 2026 The Authors. Published by Elsevier Masson SAS on behalf of SocieteFranc & cedil;aise de Nutrition (SFN). This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).

The degenerative loss of muscle associated with aging leading to muscular atrophy is called sarcopenia. Currently, practicing regular physical exercise is the only efficient way to delay sarcopenia onset. Identification of therapeutic targets to alleviate the symptoms of aging requires in vivo model organisms of accelerated muscle degeneration and atrophy. The zebrafish undergoes aging, with hallmarks including mitochondrial dysfunction, telomere shortening, and accumulation of senescent cells. However, zebrafish age slowly, and no specific zebrafish models of accelerated muscle atrophy associated with molecular events of aging are currently available. We have developed a new genetic tool to efficiently accelerate muscle-fiber degeneration and muscle-tissue atrophy in zebrafish larvae and adults. We used a gain-of-function strategy with a molecule that has been shown to be necessary and sufficient to induce muscle atrophy and a sarcopenia phenotype in mammals: Atrogin-1 (also named Fbxo32). We report the generation, validation, and characterization of a zebrafish genetic model of accelerated neuromuscular atrophy, the atrofish. We demonstrated that Atrogin-1 expression specifically in skeletal muscle tissue induces a muscle atrophic phenotype associated with locomotion dysfunction in both larvae and adult fish. We identified degradation of the myosin light chain as an event occurring prior to muscle-fiber degeneration. Biological processes associated with muscle aging such as proteolysis, inflammation, stress response, extracellular matrix (ECM) remodeling, and apoptosis are upregulated in the atrofish. Surprisingly, we observed a strong correlation between muscle-fiber degeneration and reduced numbers of neuromuscular junctions in the peripheral nervous system, as well as neuronal cell bodies in the spinal cord, suggesting that muscle atrophy could underly a neurodegenerative phenotype in the central nervous system. Finally, while atrofish larvae can recover locomotive functions, adult atrofish have impaired regenerative capacities, as is observed in mammals during muscle aging. In the future, the atrofish could serve as a platform for testing molecules aimed at treating or alleviating the symptoms of muscle aging, thereby opening new therapeutic avenues in the fight against sarcopenia.

Postoperative neurocognitive disorder (PND) is characterized by cognitive deficits that emerge after surgery. Although often reversible within weeks or months, PND can persist and lead to significant central dysfunction and an increased risk of dementia. Given that obesity is a chronic low-grade inflammatory condition previously associated with structural and functional brain alterations, we hypothesized and demonstrated that it could be a significant risk factor for PND. We assessed the incidence of PND and cognitive performance in obese individuals undergoing cardiac or orthopedic surgeries. In parallel, we developed a preclinical model combining diet-induced obesity in mice with surgically induced tibial fracture. Pharmacological (ketoprofen), surgical (adipose tissue ablation), and behavioral (calorie restriction) interventions were used to target obesity-associated inflammation. Compared with nonobese individuals, obese patients presented a greater incidence of early postoperative cognitive changes and lower cognitive performance (p < 0.009). In mice, the combination of obesity and surgery results in exacerbated signs of PND. Importantly, obesity-related PND in mice was prevented by interventions that reduced central and systemic inflammation. These findings identify obesity-driven fat mass and inflammation as strong risk factors for PND for the first time. Targeting obesity-associated inflammatory mechanisms may represent an effective strategy to reduce the incidence of this debilitating postoperative condition.

IntroductionImbalance in the redox equilibrium is common in any type of aggression. Cardiopulmonary bypass (CPB) initiation induces metabolic perturbations, and reliable biological monitoring tools for this condition are currently limited (e.g., lactate/pyruvate ratio). The measurement of arterial whole blood redox potential (Eredox) provides a systemic assessment of the redox state and may serve as a valuable marker for detecting metabolic perturbations during CPB. In this prospective exploratory study involving patients undergoing cardiac surgery, we investigated variations in Eredox and lactate/pyruvate ratio during CPB initiation.MethodsUsing a prospective exploratory study design, we assessed the changes in Eredox and relevant variables during the initiation of CPB in 16 cardiac surgery patients.ResultsUpon initiation of CPB we observed a significant decrease in arterial whole blood redox potential (101.90 mV + /- 11.52 vs. 41.80 mV + /- 10,26; p < 0.0001). Concomitantly, the lactate/pyruvate ratio significantly increased (12.81 + /- 0.90 vs 67.1 + /- 7.94; p < 0.0001) while the acetoacetate/β-hydroxybutyrate ratio significantly decreased (1.11 + /- 0.19 vs. 0.54 + /- 0.05 at 0 min; p = 0.0055). The circulatory failure indicated by changes in the lactate/pyruvate ratio and ketone bodies at the initiation of CPB correlated with a significant reduction in Eredox.ConclusionArterial Eredox is a novel variable that holds promise in the detection and monitoring of metabolic aggression during CPB. Its assessment during CPB initiation could provide valuable insights into the patient's circulatory status, as the Eredox appears to be more sensitive than lactate for monitoring circulatory insufficiency.

Non-shivering thermogenesis in brown adipose tissue (BAT) is linked to metabolic health. Yet, how its activity states impact on systemic metabolism and in particular on lactate, a highly abundant metabolite increasingly recognized as a critical player in energy metabolism, remains unresolved. The goal of this study was to investigate the impact of BAT activity on lactate metabolism at the whole organism level. To activate or inactivate non-shivering thermogenesis in BAT, we housed C57Bl6/J male mice at 4, 21 and 30°C and then conducted lactate tolerance tests. In mice exposed to cold exposure (4°C), systemic lactate clearance was elevated. In contrast, clearance of systemic lactate was poor in mice housed under thermoneutral conditions (30°C) that inactivate BAT thermogenesis, as well as in mice deficient for the mitochondrial uncoupling protein-1. To better understand lactate metabolic fate during the clearance phase, in vivo stable isotope tracing experiments with labelled 13C-lactate and analyses by mass spectrometry were performed. These experiments revealed that lactate contribution to gluconeogenesis was increased under cold exposure while its contribution to the tricarboxylic acid cycle was reduced in BAT under thermoneutrality. Remarkably, we also identified that lactate entered a pyruvate cycling process that was highly active in BAT, and repressed at thermoneutrality. Our study shows that inactivation of non-shivering thermogenesis decreased systemic lactate clearance, concomitantly with changes in metabolic fate of lactate in BAT and in gluconeogenic organs, in male mice. KEY POINTS: Lactate clearance is enhanced upon cold exposure and reduced at thermoneutrality. UCP1-deficient mice exhibit impaired lactate clearance. Oxidative utilization of lactate in brown fat is decreased at thermoneutrality. Prolonged cold exposure increases lactate contribution to gluconeogenesis. Lactate enters a highly active pyruvate cycling process in brown adipose tissue.

Multivariate analysis of the TUH cohort

Aging leads to a decline in physiological reserves, an increase in age-related diseases, reduced functional ability and a shortened healthspan. While molecular markers of chronological aging exist, their link to general health and intrinsic capacity (IC), a composite measure of physical and mental capacities, remains unclear. This study integrates the WHO's Healthy Aging framework with geroscience to explore fibroblasts as indicators of health. We assessed primary skin fibroblasts from 133 individuals aged 20-96, evaluating their ability to maintain tissue structure, modulate immune responses and regulate metabolism (SIM functions). By combining functional and molecular analyses, we investigated the relationship between fibroblast performance, chronological age and IC. Our results demonstrate that fibroblast SIM functions are modified with stressors and age, correlating with IC rather than just chronological age. Notably, fibroblasts from pre-frail and frail individuals exhibited reduced mitochondrial respiration and lower extracellular periostin levels, with periostin being able to capture IC status, irrespective of age and sex, reflecting a cellular 'health memory'. The SIM paradigm provides a complementary framework to the established hallmarks of aging, advancing our understanding of how cellular aging impacts functional decline. These findings suggest that fibroblast-derived markers could serve as indicators of frailty and reduced IC, enabling early detection of individuals at risk for health deterioration and laying the foundation for early identification of functional decline.

Human antibodies for flow cytometry analyses (TUH cohort)

Human antibodies for flow cytometry analyses (TUH cohort)

HealthAge was devised by a conglomerate of research groups in Toulouse, France, with the combined goal of narrowing the lifespan-healthspan gap through novel translational bench-to-bedside research studies. HealthAge comprises the “INStitute for Prevention” “healthy aging” and “medicine Rejuvenative” (INSPIRE) human translational, outbred SWISS mice and African turquoise killifish (GRZ strain) cohorts in which aging is studied based on the concept of intrinsic capacity (IC). In this narrative review, we describe the three INSPIRE aging models (human cohort, n = 1109, age range 20 –102 years old with mean age ± standard deviation, 62.4 ± 19.0 years and 61.9

Background Out-of-hospital cardiac arrest (OHCA) represents a major burden for society and health care, with an average incidence in adults of 67 to 170 cases per 100,000 person-years in Europe and in-hospital survival rates of less than 10%. Patients and practitioners would benefit from a prognostication tool for long-term good neurological outcomes. Objective We aim to develop a machine learning (ML) pipeline on a local database to classify patients according to their neurological outcomes and identify prognostic features. Methods We collected clinical and biological data consecutively from 595 patients who presented OHCA and were routed to a single regional cardiac arrest centre in the south of France. We applied recursive feature elimination and ML analyses to identify the main features associated with a good neurological outcome, defined as a Cerebral Performance Category score less than or equal to 2 at six months post-OHCA. Results We identified 12 variables 24 h after admission, capable of predicting a six-month good neurological outcome. The best model (extreme gradient boosting) achieved an AUC of 0.96 and an accuracy of 0.92 in the test cohort. Conclusion We demonstrated that it is possible to build accurate, locally optimised prediction and prognostication scores using datasets of limited size and breadth. We proposed and shared a generic machine-learning pipeline which allows external teams to replicate the approach locally.

Abstract Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematological malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.

Introduction:Within adipose tissue (AT), different macrophage subsets have been described, which played pivotal and specific roles in upholding tissue homeostasis under both physiological and pathological conditions. Nonetheless, studying resident macrophages in-vitro poses challenges, as the isolation process and the culture for extended periods can alter their inherent properties. Methods:Stroma-vascular cells isolated from murine subcutaneous AT were seeded on ultra-low adherent plates in the presence of macrophage colony-stimulating factor. After 4 days of culture, the cells spontaneously aggregate to form spheroids. A week later, macrophages begin to spread out of the spheroid and adhere to the culture plate. Results:This innovative three-dimensional (3D) culture method enables the generation of functional mature macrophages that present distinct genic and phenotypic characteristics compared to bone marrow-derived macrophages. They also show specific metabolic activity and polarization in response to stimulation, but similar phagocytic capacity. Additionally, based on single-cell analysis, AT-macrophages generated in 3D culture mirror the phenotypic and functional traits of in-vivo AT resident macrophages. Discussion:Our study describes a 3D in-vitro system for generating and culturing functional AT-resident macrophages, without the need for cell sorting. This system thus stands as a valuable resource for exploring the differentiation and function of AT-macrophages in vitro in diverse physiological and pathological contexts.

Alzheimer's disease is strongly linked to metabolic abnormalities. We aimed to distinguish amyloid-positive people who progressed to cognitive decline from those who remained cognitively intact. We performed untargeted metabolomics of blood samples from amyloid-positive individuals, before any sign of cognitive decline, to distinguish individuals who progressed to cognitive decline from those who remained cognitively intact. A plasma-derived metabolite signature was developed from Supercritical Fluid chromatography coupled with high-resolution mass spectrometry (SFC-HRMS) and nuclear magnetic resonance (NMR) metabolomics. The 2 metabolomics data sets were analyzed by Data Integration Analysis for Biomarker discovery using Latent approaches for Omics studies (DIABLO), to identify a minimum set of metabolites that could describe cognitive decline status. NMR or SFC-HRMS data alone cannot predict cognitive decline. However, among the 320 metabolites identified, a statistical method that integrated the 2 data sets enabled the identification of a minimal signature of 9 metabolites (3-hydroxybutyrate, citrate, succinate, acetone, methionine, glucose, serine, sphingomyelin d18:1/C26:0 and triglyceride C48:3) with a statistically significant ability to predict cognitive decline more than 3 years before decline. This metabolic fingerprint obtained during this exploratory study may help to predict amyloid-positive individuals who will develop cognitive decline. Due to the high prevalence of brain amyloid-positivity in older adults, identifying adults who will have cognitive decline will enable the development of personalized and early interventions.

Aging is characterized by several major changes, including altered body composition, which is associated with numerous negative clinical consequences such as sarcopenia, osteoporosis, and frailty. The study is to evaluate body composition parameters depending on age and sex in a population ranging from the young adult to the very old, and to identify break points in the association between body composition and age. In this cross-sectional study, we included the enrolment population of the French INSPIRE-T prospective cohort, accounting for 915 subjects (62

Identifying mechanisms underlying relapse is a major clinical issue for effective cancer treatment. The emerging understanding of the importance of metastasis in hematologic malignancies suggests that it could also play a role in drug resistance and relapse in acute myeloid leukemia (AML). In a cohort of 1,273 AML patients, we uncovered that the multifunctional scavenger receptor CD36 was positively associated with extramedullary dissemination of leukemic blasts, increased risk of relapse after intensive chemotherapy, and reduced event-free and overall survival. CD36 was dispensable for lipid uptake but fostered blast migration through its binding with thrombospondin-1. CD36-expressing blasts, which were largely enriched after chemotherapy, exhibited a senescent-like phenotype while maintaining their migratory ability. In xenograft mouse models, CD36 inhibition reduced metastasis of blasts and prolonged survival of chemotherapy-treated mice. These results pave the way for the development of CD36 as an independent marker of poor prognosis in AML patients and a promising actionable target to improve the outcome of patients.SIGNIFICANCE:CD36 promotes blast migration and extramedullary disease in acute myeloid leukemia and represents a critical target that can be exploited for clinical prognosis and patient treatment.