Chemokines are small cytokines that are essential for recruiting immune cells and modulating inflammatory responses. Their expression and activity are tightly regulated by redox homeostasis, which influences cellular signaling and immune function through dynamic interactions with reactive oxygen and nitrogen species (ROS and RNS). Redox-sensitive transcription factors, such as NF-κB, and post-translational modifications, including glutathionylation, help fine-tune chemokine expression and receptor activity. Conversely, chemokines and their receptors also affect cellular oxidative states, notably by modulating ROS production via NADPH oxidase activation.This review explores the bidirectional interplay between chemokine signaling and redox homeostasis, particularly focusing on how this relationship shapes the progression of aging and age-related diseases. By synthesizing findings from clinical studies, preclinical models, and mechanistic investigations published in the last five years, we highlight the relevance of chemokine-redox interactions in conditions such as Alzheimer’s disease and atherosclerosis. Finally, we discuss emerging therapeutic approaches that modulate both chemokine signaling and oxidative stress to restore immune balance and mitigate age-associated tissue damage.

Introduction:Oxidative stress, driven by the imbalance between reactive species from oxygen and nitrogen and antioxidant defense mechanisms, plays a pivotal role in aging-related pathologies. Structured multicomponent exercise interventions have mitigated hospital-acquired disability by improving physical and cognitive function and quality of life. However, the underlying molecular mechanisms of this improvement remain partially understood. Methods:We conducted a secondary analysis of a randomized controlled trial to investigate the impact of a supervised exercise program on oxidative stress in hospitalized older adults. Participants were randomized to a 3-day tailored exercise program based on baseline functional capacity. Serum malondialdehyde (MDA) levels (μmol/mL) and the oxidative oxidation of total proteins (PO) were measured. RESULTS: Seventy-two participants were included in this subanalysis (mean age 86.8 years [SD 4.96], 53.8% female [n = 39]). The exercise group showed a minimal change in MDA levels, while the control group exhibited a significant increase, with a between-group difference of -0.24 μmol/mL (p < 0.01). Subgroup analyses demonstrated significant benefits in patients with diabetes and in women. The intervention improved functional capacity and subjective health status. Participants with lower baseline oxidative stress levels showed greater improvement in SPPB compared to those with higher baseline levels. Discussion:Structured exercise may mitigate the increase in oxidative stress in hospitalized older adults, particularly in women and those with diabetes. The magnitude of functional improvements could depend on baseline oxidative status, highlighting the need for personalized interventions. Future research should explore long-term effects, biomarkers, and tailored protocols to optimize outcomes in this population.

Alzheimer’s disease (AD) diagnosis often relies on invasive or costly techniques such as cerebrospinal fluid sampling and PET imaging. Peripheral blood biomarkers could offer a minimally invasive and accessible alternative. We aimed to evaluate the diagnostic and prognostic value of four candidate biomarkers—Clusterin, RCAN1, RAGE, and MDA—in the context of cognitive decline, and to generate a predictive model for AD diagnosis. We conducted longitudinal and cross-sectional analyses among participants in the Vallecas Project (Spain). For longitudinal analyses, 52 subjects with paired baseline and 5-year follow-up samples were classified as stable cognitively healthy controls, MCI converters, or AD progression. Cross-sectional analyses were conducted using a single observation per subject (n = 83) selected to reduce age differences between the three groups, although AD patients were significantly older. Biomarker levels were measured in plasma or serum by ELISA (Clusterin, RCAN1, RAGE) or UPLC (MDA). A predictive model for AD diagnosis was developed using penalized logistic regression based on baseline data from 76 subjects, incorporating biomarkers, age, sex, and APOE ε4 genotype. In the longitudinal analysis, RCAN1 levels decreased significantly over time in cognitively stable controls, whereas Clusterin levels decreased in the AD progression group. No significant longitudinal changes were observed in MCI converters. In the cross-sectional analysis, RCAN1 and MDA levels were significantly lower in AD patients than in cognitively healthy controls and MCI patients. RAGE levels showed a trend toward reduction in MCI but did not remain significant. At baseline, cognitively healthy individuals who later converted to MCI exhibited higher MDA levels and lower RAGE levels than stable controls. The predictive model achieved a mean cross-validated accuracy of approximately 92

Over the past century, research on vitamin E has evolved from its initial identification as a fertility factor to the recognition of α-tocopherol (α-TOH) as an essential micronutrient with antioxidant and gene regulatory functions. Despite extensive investigation, controversies persist regarding its precise biological role, clinical efficacy, and classification as a vitamin.This review summarizes scientific milestones in vitamin E (tocochromanol) research. It highlights recent advances in understanding the absorption, metabolism, and molecular mechanisms of vitamin E. The review also outlines unresolved questions and methodological challenges. The focus is on α-TOH and its metabolites, which exhibit biological activities beyond classical antioxidant effects, such as the regulation of inflammation, lipid metabolism, and immune responses.Evidence from genetic, biochemical, and clinical studies supports the essentiality of α-TOH in humans, as demonstrated by ataxia with vitamin E deficiency (AVED). Other tocochromanols and their metabolites exhibit promising biological activities that suggest potential therapeutic applications. However, their physiological relevance must be confirmed. Advances in metabolomic profiling and molecular modeling now allow for a more comprehensive characterization of vitamin E metabolism and function.Understanding the molecular pathways and biological roles of vitamin E and its derivatives is crucial for refining its definition, establishing evidence-based dietary recommendations, and evaluating its potential in disease prevention and therapy.

Aging entails a progressive decline in physiological functions, elevating the risk of age-related diseases like heart failure or aortic stenosis. Stem cell therapies, especially those that use paracrine signaling, can potentially mitigate the adverse effects of aging. The objective is to explore the potential of small extracellular vesicles (sEVs) derived from young adipose-derived stem cells (ADSC-sEVs) in reversing structural, molecular, and functional changes associated with aging in the heart. Aged C57BL/6J mice were treated intravenously with ADSC-sEVs from young mice or PBS as controls. Young mice were included to identify specific age-associated changes. The impact of sEV treatment on cardiac function was assessed using transthoracic echocardiography and physical endurance tests. Histological and molecular analyses were conducted on heart tissue to evaluate structural changes and markers of senescence, inflammation, and oxidative stress. A comprehensive metabolomic analysis was also performed on heart tissues to identify changes in metabolic profiles associated with aging and treatment status. The administration of ADSC-sEVs significantly improves several aging-associated cardiac parameters, including oxidative stress, inflammation, and cellular senescence reductions. We also report on the age-related reversal of myocardial structure and function changes, highlighted by decreased fibrosis and improved vascularization. Notably, echocardiographic assessments reveal that sEV treatments ameliorate diastolic dysfunction and left ventricle structural alterations typically associated with aging. Furthermore, the treatment shifts the heart metabolome towards a more youthful profile. These results denote the potential of ADSC-sEVs as a novel, noninvasive therapeutic strategy for mitigating cardiac aging-associated functional decline.

Extracellular vesicles (EVs) are emerging as key regulators of cellular communication, with increasing evidence supporting their role in oxidative stress (OS) modulation. In particular, the miRNA cargo of EVs plays a crucial role in mitigating OS and promoting redox balance through both direct antioxidant effects and epigenetic regulation. This study aimed to evaluate the impact of EVs on OS markers, influenced by their miRNA-mediated effects and potential epigenetic modifications in target cells. A systematic literature search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines to identify studies reporting the effects of EVs on OS parameters. A meta-analysis was performed on key OS biomarkers, including reactive oxygen species (ROS), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). The heterogeneity of EV isolation and characterization techniques was also analyzed. The included studies demonstrated that EVs exert significant antioxidant effects by reducing ROS levels, increasing SOD activity and GSH levels, and lowering MDA levels. These effects were largely attributed to EV-miRNAs, which induce epigenetic modifications that modulate redox-related signaling pathways. However, the variability in EV isolation methods and characterization approaches highlights the need for standardization to improve data comparability. Despite their therapeutic potential, this significant heterogeneity in EV research remains a barrier to translation. Moreover, further exploration of epigenetic mechanisms is essential to fully harness their benefits for OS-related diseases.

Our previous transcriptomic analysis revealed an up-regulation of the antiapoptotic protein B cell lymphoma-extra large (Bcl-xL) in centenarians relative to octogenarians or younger cohorts. In this study, we used Bcl-xL-overexpressing mice to assess its impact on successful aging. Our findings indicate that Bcl-xL overexpression modifies T cell subsets and improves their metabolism, apoptosis resistance, macroautophagy, and cytokine production during aging. This more resilient immune system reduces inflammation and preserves mitochondrial integrity and function in muscle tissue, thereby retarding the onset of frailty. These results underscore the important contribution of Bcl-xL to healthy aging, a phenomenon that is conserved across mammalian species.

The study by Bi et al. (2025) presents “Senoreverse”, an innovative strategy that utilizes exosomal miR-302b to restore the proliferative capacity of senescent cells (SnCs), thus extending lifespan and enhancing cognitive and physical function in aging mice without the risk of tumorigenicity.

Traumatic brain injury (TBI) is one of the leading causes of disability worldwide. Clinical or imaging scales are currently used to stratify severity, but they show a limited correlation with clinical prognosis, which has raised interest in biomarkers. Extracellular vesicles (EV)-based biomarkers may be superior to soluble biomarkers because of their stability, resistance to degradation and unique signature according to tissue of origin. Identification of EV-associated TBI biomarkers remains challenging due to the significant heterogeneity in experimental design, exosome isolation methods and study populations. This systematic review aims to analyze the role of EVs as biomarkers in TBI across both animal and clinical models, with particular focus on their association with prognosis. A systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Four electronic databases were searched from inception to December 31st, 2024, using the terms “traumatic brain injury”, “extracellular vesicles” and “biomarkers”. Animal studies and human cohort, case control, and case series studies were included; previous reviews, congress abstracts, and non-peer-reviewed works were excluded. Studies conducted on adult individuals or in experimental models of acute TBI, regardless of the mechanism and severity, and which studied biomarkers within the first week of injury, were included. The primary outcome was the EV-based biomarker identified by each study and its diagnostic accuracy when provided. Secondary outcomes were sample type for EV isolation, origin of EVs and methods for isolation and characterization. A total of 18 animal and 19 human studies were included. miRNAs were the most frequently identified biomarker in animal studies, while proteins were most common in human studies. The most commonly identified proteins in EVs were GFAP, UCH-L1, and Tau, with miRNA-124-3p also being repeatedly found. EVs were most frequently obtained from plasma, followed by brain tissue lysates in animals and cerebrospinal fluid or saliva in humans. Most studies used ultracentrifugation or polymer-based precipitation for EV isolation, with western blotting and electron microscopy for characterization. Few studies provided a measure of accuracy for the studied biomarkers; the highest diagnostic performance has been achieved with neural EV-based miRNA panels. While several studies explored diagnostic applications, only a limited number investigated prognostic utility, with few using scales such as GOS-E or evaluating long-term neurocognitive complications. This review highlights the potential of EV-based biomarkers in TBI, emphasizing their stability and tissue-specific signatures. Standardized protocols for EV isolation and characterization are needed for consistency across studies. While diagnostic applications have been explored, more research is required on the prognostic value of EV biomarkers, particularly for neurological outcomes, with future studies incorporating performance metrics to assess their clinical relevance.

Graphical abstract Abstract BackgroundOxidative stress plays a crucial role in the pathophysiology of impaired wound healing. Indeed, it has been the focus of different therapeutic interventions, which have been explored primarily for their potential to enhance tissue repair. This systematic review and meta-analysis aimed to evaluate the effects of various therapeutic interventions on oxidative stress markers and wound healing parameters in clinical wound models.MethodsA comprehensive literature search was conducted in PubMed (2015–2025), identifying 21 eligible studies that assessed oxidative stress-related systemic or topical treatments in clinical models of acute or chronic wounds. The risks of bias in the studies were analyzed using the Cochrane RoB 2 tool. Data were extracted on oxidative stress biomarkers (e.g. MDA, SOD, and GSH) and wound healing outcomes (e.g. wound closure rate and histological scores). Meta-analyses were performed using random-effects models, and heterogeneity was assessed using the I2 statistic. Outcomes were evaluated with the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system.ResultsMost interventions demonstrated significant reductions in oxidative stress markers and improvements in wound healing metrics compared to controls. The meta-analysis revealed a pooled effect favoring treated groups in both biochemical and morphological outcomes, although with moderate heterogeneity across studies.ConclusionThe therapeutic efficacy related to oxidative stress in wound healing outcomes may be attributable, at least in part, to consistently enhanced antioxidant profiles and reduced oxidative stress markers. These findings support the need for further translational research into antioxidant-based therapies for wound management.

Extracellular vesicles (EVs) are nanoscale particles released by cells into body fluids and serve as crucial mediators of intercellular communication. This chapter explores their biogenesis, cargo composition, and biological functions on target cells. It discusses the diverse molecular cargo of EVs that includes lipids, proteins, and nucleic acid and focuses on their sorting, analysis, and functional significance. It highlights their importance as biomarkers as diagnostic and prognostic tools, particularly their potential application in clinical chemistry. The chapter also provides an overview of the current techniques for isolating and characterizing EVs from various body fluids and recent technological advancements. It compares EV and liquid biopsy biomarkers, outlines their advantages and limitations, and examines their translational impact on personalized medicine. Furthermore, this chapter emphasizes the clinical relevance of EV biomarkers, especially in monitoring aging, evaluating anti-aging therapy, and diagnosing age-related diseases such as neurodegenerative, cardiovascular, and musculoskeletal disorders. The chapter concludes with a critical discussion about the potential of EV research to revolutionize clinical diagnostics, which unfortunately remains constrained by regulatory hurdles and a lack of standardization.

The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.

Aging is the outcome of the gradual accumulation of changes within an organism over time, resulting in a decline in biological function. It is a universal phenomenon that affects all living organisms and is characterized by a progressive reduction in both physical and mental capabilities, which is associated with an increased susceptibility to illness and mortality (Viña et al. in IUBMB Life. 59:249–254, 2007; Guo et al. in Signal Transduct Target Ther. 7:391, 2022; Partridge in Philosophical transactions of the Royal Society of London Series B, Biological sciences. 365:147–154, 2010;). The biological process of aging is a complex phenomenon that occurs due to the accumulation of a variety of molecular and cellular damages over time.

In an era of rising global life expectancies, research focuses on enhancing the quality of extended years. This review examines the link between mitochondrial function and aging, highlighting the importance of healthspan alongside lifespan. This involves significant human and economic challenges, with longer lifespans often accompanied by reduced well‐being. Addressing mitochondrial decline, exploring targeted interventions, and understanding the complexities of research models are vital for advancing our knowledge in this field. Additionally, promoting physical exercise and adopting personalized supplementation strategies based on individual needs can contribute to healthy aging. The insights from this Perspective article offer a hopeful outlook for future advances in extending both lifespan and healthspan, aiming to improve the overall quality of life in aging populations.

In this review, we examine the role of oxidative stress in the pathophysiology of Alzheimer's Disease (AD). Amyloid-beta (Aβ) induces damage not only extracellularly but also within the intracellular environment. Mitochondria, a principal source of free radicals, are closely associated with Aβ, as it binds to heme, thereby disrupting the normal electron flow in the respiratory chain. At the turn of the century, it was hypothesized that the majority, if not all, pathological events in AD are linked to free radical damage. Notably, free radicals also possess signaling capabilities that contribute to the disease's progression. A substantial body of evidence suggests that radical signaling is implicated in the relationship between amyloid-β and tau hyperphosphorylation. Antioxidant therapy represents a potential strategy to delay the progression from cognitive impairment to overt dementia. Enhancing endogenous antioxidant defenses, for instance, through polyphenol supplementation, offers a promising approach to partially prevent dementia onset, particularly in at-risk populations. Understanding the redox-related pathophysiology of AD opens new avenues for prevention and treatment, providing a source of hope in the fight against Alzheimer's Disease.

Centenarians and their relatives possess a notable survival advantage, with higher longevity and reduced susceptibility to major age-related diseases. To date, characteristic omics profiles of centenarians have been described, demonstrating that these individuals with exceptional longevity regulate their metabolism to adapt and incorporate more resilient biomolecules into their cells. Among these adaptations, the lipidomic profile stands out. However, it has not yet been determined whether this lipidomic profile is specific to centenarians or is the consequence of extreme longevity genetics and is also present in centenarians' offspring. This distinction is crucial for defining potential therapeutic targets that could help delay the aging process and associated pathologies. We applied mass-spectrometry-based techniques to quantify 569 lipid species in plasma samples from 39 centenarians, 63 centenarians' offspring, and 69 noncentenarians' offspring without familial connections. Based on this profile, we calculated different indexes to characterize the functional and structural properties of plasma lipidome. Our findings demonstrate that extreme longevity genetics (centenarians and centenarians' offspring) determines a specific lipidomic signature characterized by (i) an enrichment of hexosylceramides, (ii) a decrease of specific species of ceramides and sulfatides, (iii) a global increase of ether-PC and ether-LPC, and (iv) changes in the fluidity and diversity of specific lipid classes. We point out the conversion of ceramides to hexosylceramides and the maintenance of the levels of the ether-linked PC as a phenotypic trait to guarantee extreme longevity. We propose that this molecular signature is the result of an intrinsic adaptive program that preserves protective mechanisms and cellular identity.