bims-mistre 2026-04-12 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–04–12
24 papers selected by
Ellen Siobhan Mitchell, MitoQ

Associations of Elevated Red Cell Distribution Width (RDW) with Decreased Physical and Cognitive Function in Older Adults, and The Potential Mediation by Mitochondrial Energetics: The Study of Muscle, Mobility and Aging (SOMMA).
Mitochondrial dysfunction in Alzheimer's disease and related sex differences.
High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment.
Interplay of Skin Aging: Mitochondrial Stress and Ultraviolet Exposure.
Oocyte aging in focus: Environmental and endogenous stressors driving reproductive potential decline.
Declining nitric oxide bioavailability in cardiovascular aging: mechanistic insights and emerging interventions.
APOE4 Accelerates Menopause-Associated Brain Metabolic Shift and Disrupts Bioenergetic Adaptation.
Exercise Attenuates Neuroinflammation in Chronic Restraint Stress Induced Depression Model by Downregulating GDF15 Expression.
SIRT1 Activators as Geroprotective Agents in Brain Aging: Mechanisms and Therapeutic Potential.
Vitamin B3 rescues mitochondrial homeostasis in dexamethasone-induced skeletal muscle atrophy by reducing oxidative stress.
Exercise induces sex-specific assembly of mitochondrial supercomplexes.
The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.
Phenolics-Rich Extract From Agarwood (Aquilaria sinensis) Leaf-Tea Alleviates Hyperglycemia in Type 2 Diabetes Mellitus Mice via Modulating Lipid Metabolism and Gut Microbiota.
Mitochondria-Targeted Liposomes Boost Thermogenesis for Adipose Tissue Regulation.
Impact of miR-181a-5p and miR-1249-3p treatment on the visceral adipose tissue transcriptome of female mice.
Sex differences in response to longevity interventions.
Carnitine deficiency alters fuel metabolism and voluntary wheel running in mice.
Metabolic Phenotype Predicts Biochemical Response to Inositol Supplementation in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.
From Defence to Dysfunction: The Dual Role of Autophagy and Mitophagy in Cardiomyopathy.
Estrogen signaling processes in fibroblasts: a scoping review.
The Role of Estradiol in Oxidative Stress in Health and Cystathionine ß-Synthase Deficiency: A Mechanistic Model.
Metabolic Adaptations to Caloric Restriction: Time- and Group-Dependent Metabolomic Signatures from the CALERIE™ Trial.
Double-Pronged NAD Preservation: Delaying Cellular Senescence and Initiating Musculoskeletal Regeneration.
Brain energetic landscapes shape state dysregulation in major depressive disorder: a morphological network controllability perspective.

Aging Dis. 2025 Apr 22. 17(3): 1654-1663

Associations of Elevated Red Cell Distribution Width (RDW) with Decreased Physical and Cognitive Function in Older Adults, and The Potential Mediation by Mitochondrial Energetics: The Study of Muscle, Mobility and Aging (SOMMA).

Kyoung Min Kim, Li-Yung Lui, Theresa Mau, Paul M Coen, Steven R Cummings.

We analyzed the association between RDW and skeletal muscle mitochondrial energetics and how skeletal muscle mitochondrial energetics may mediate the associations of RDW with physical and cognitive performance. The study analyzed cross-sectional baseline data from the Study of Muscle, Mobility and Aging (SOMMA) that enrolled 864 participants aged 70 and older (mean=76.3 years). RDW, clinical and demographic parameters were assessed. Comprehensive evaluations were conducted for both physical and cognitive function using objective and subjective measures. Elevated RDW values were significantly correlated with decreased physical performance, evidenced by reduced cardiorespiratory fitness (VO2peak) and longer time to 400 m Walk, alongside impaired cognitive performance. Higher RDW values also demonstrated robust negative associations with various measurements of mitochondrial energetics, including maximal ATP production and oxidative phosphorylation. Mediation analysis revealed that impaired mitochondrial function partly mediated the associations between RDW values and VO2peak, and other physical and cognitive performance. These findings suggest that higher RDW is associated with declines in various physical and cognitive performance, with skeletal muscle mitochondrial energetics serving as a potential mediating factor. Causal inferences about potential mediation are limited by the cross-sectional design of the study. Nevertheless, the findings highlight the value of RDW as a potential biomarker for age-related declines in physical and cognitive function partly mediated by mitochondrial energetics.

DOI: https://doi.org/10.14336/AD.2024.1724
Front Aging Neurosci. 2026 ;18 1761702

Mitochondrial dysfunction in Alzheimer's disease and related sex differences.

Afzal Misrani, Conelius Ngwa, Fudong Liu.

  Alzheimer's disease (AD), the most common form of dementia, accounts for 70% of cases and remains a major healthcare challenge due to its rising prevalence and lack of disease-modifying treatments. Clinically, AD is a sexually dimorphic disease. Women exhibit more rapid cognitive decline and accelerated brain atrophy during mild cognitive impairment and early dementia, whereas men more frequently present cardiovascular comorbidities, earlier mitochondrial dysfunction, and greater neuropsychiatric symptoms. AD is marked by amyloid-β (Aβ) plaques, neurofibrillary tangles, neuroinflammation, and neuronal loss, with mitochondrial dysfunction emerging as a key early contributor that exhibits sex specific phenotypes. Mitochondria are vital for neuronal function by generating ATP, maintaining calcium homeostasis, and regulating oxidative stress. However, mitochondria in AD exhibit impaired ATP synthesis, excessive reactive oxygen species (ROS) production, calcium dysregulation, and disrupted fission-fusion dynamics. AD mitochondrial dysfunction can be measured by molecular markers, such as increased expression of fission-related protein Drp1, decreased biogenesis regulator PGC-1α, and elevated oxidative stress markers like malonaldehyde, nitotyrosine and protein carbonyls. Accumulating data suggest that sex differences in mitochondrial dysfunction are attributed to either sex hormonal or sex chromosomal effects, which eventually contribute to sex dichotomic phenotypes of AD. This review collected data regarding mitochondrial dysfunction in AD, with an emphasis on sex differences in oxidative stress, energy metabolism, and regulatory pathways.

Keywords:  Alzheimer's disease; dementia; mitochondria; oxidative stress; sex differences

DOI:  https://doi.org/10.3389/fnagi.2026.1761702
Cell Biochem Funct. 2026 Apr;44(4): e70211

High Glucose Triggers Macrophage Senescence Through Mitochondrial Dysfunction and Mitophagy Impairment.

Liying Tang, Xiuting Huang, Pei Li.

  Chronic hyperglycemia accelerates immune aging and contributes to diabetic complications, yet the mitochondrial mechanisms responsible for macrophage senescence remain unclear. In this study, both cultured and primary macrophages were treated with high glucose to model hyperglycemic conditions. High glucose significantly increased markers of macrophage senescence, including SA-β-Gal staining, expression of p16 and p21, and secretion of pro-inflammatory cytokines. Mitochondrial dysfunction was evident, as shown by loss of mitochondrial membrane potential (ΔΨm) and elevated mitochondrial reactive oxygen species (mtROS). In addition, mitophagy was impaired, with PINK1 accumulation and reduced Parkin recruitment. Rescue experiments demonstrated that treatment with the mitochondria-targeted antioxidant MitoTempo, the general antioxidant N-acetylcysteine, or the anti-diabetic drug metformin effectively restored mitochondrial function and alleviated senescence. These findings indicate that mitochondrial dysfunction and impaired mitophagy are central to high glucose-induced macrophage senescence, and that targeting mitochondrial oxidative stress with antioxidants or metformin may offer a promising strategy to mitigate immune aging and inflammation associated with metabolic disorders.

Keywords:  high glucose; inflammation; macrophage; mitophagy; senescence

DOI:  https://doi.org/10.1002/cbf.70211
Photodermatol Photoimmunol Photomed. 2026 May;42(3): e70089

Interplay of Skin Aging: Mitochondrial Stress and Ultraviolet Exposure.

Wanxing Liao, Yihao Wang, Yiping Wang, Junlin Liao, Nian Chen, Chiyu Jia, Li Zeng.

   BACKGROUND: Skin photoaging, clinically characterized by wrinkles and hyperpigmentation, accounts for 80% of extrinsic aging. Chronic UV exposure drives this process via oxidative damage. However, its synergistic axis with mitochondrial dysfunction remains mechanistically elusive. This study aims to elucidate the mechanistic link between mitochondrial oxidative stress and UV-induced photoaging, focusing on reactive oxygen species overproduction as a central driver of cellular decline.
METHODS: Through integrative analysis of molecular pathways and experimental validation, we investigated mitochondrial dysfunction, ROS accumulation, and UV-induced damage in skin cells. Therapeutic interventions, including mitochondrial-targeted antioxidants (e.g., MitoQ) and protective agents, were tested to assess their efficacy in restoring mitochondrial integrity and mitigating oxidative stress.
RESULTS: UV radiation exacerbates mitochondrial dysfunction by inducing ROS overproduction, mtDNA mutations and membrane permeability alterations, creating a vicious cycle that accelerates skin aging. Conversely, mitochondrial oxidative stress amplifies UV-induced damage, promoting collagen degradation and apoptosis. Interventions targeting mitochondrial function, such as MitoQ and mesenchymal stem cell-derived exosomes, significantly reduced ROS levels, preserved membrane potential, and enhanced skin resilience. Notably, PINK1/Parkin-mediated mitophagy and STAT3/p53 pathways were identified as critical regulators of mitochondrial homeostasis during photoaging.
CONCLUSION: This study clarifies the bidirectional relationship between mitochondrial stress and photoaging, highlighting ROS as a pivotal mediator. Restoring mitochondrial function via antioxidants or mitophagy enhancers offers actionable strategies to delay skin aging. These findings provide a foundation for novel anti-aging therapies with potential clinical and cosmetic applications.

Keywords:  ROS; mitochondrial; photoaging; skin aging

DOI:  https://doi.org/10.1111/phpp.70089
Geroscience. 2026 Apr 09.

Oocyte aging in focus: Environmental and endogenous stressors driving reproductive potential decline.

Katarzyna Ratajewska, Pawel Kordowitzki.

  Oocyte quality, a critical determinant of female reproductive potential, experiences a progressive decline with age, largely driven by the cumulative effects of oxidative stress and mitochondrial dysfunction. This review thoroughly synthesizes the latest evidence concerning the molecular, cellular, and environmental factors that disrupt redox homeostasis within oocytes. It particularly highlights the pivotal roles of reactive oxygen species, impaired mitochondrial metabolism, epigenetic dysregulation, and alterations in the ovarian microenvironment. We further elucidate how aging, environmental toxicants, lifestyle choices, and pathological conditions such as cystic ovaries and endometriosis exacerbate oxidative damage, thereby severely compromising meiotic competence and embryonic development. Compelling evidence from both human and animal models has shed light on the intricate mechanisms underlying ROS-induced oocyte deterioration, which will be discussed herein. Moreover, we evaluate promising emerging interventions, including antioxidant, dietary, lifestyle, and mitochondria-targeted strategies, all aimed at preserving reproductive longevity. Collectively, these insights firmly establish oxidative stress as a central and undeniable driver of oocyte aging, underscoring the urgent need for integrated biomedical and environmental strategies to safeguard female fertility.

Keywords:  Aging; Antioxidants; Environmental stressors; Mitochondria; Oocytes; Oxidative stress; ROS

DOI:  https://doi.org/10.1007/s11357-026-02243-6
J Cardiovasc Aging. 2025 ;pii: 20. [Epub ahead of print]5(4):

Declining nitric oxide bioavailability in cardiovascular aging: mechanistic insights and emerging interventions.

Hriju Adhikari, Priyanka Patel, Namratha Javvaji, Mark J Crabtree, Jillian N Simon.

  Nitric oxide (NO) is essential for maintaining normal cardiovascular function, and accumulating evidence suggests that its diminished bioavailability contributes to endothelial dysfunction, vascular stiffening, and impaired cardiac performance - hallmarks of cardiovascular aging. This review posits that reduced NO bioavailability with age stems from impaired endothelial and neuronal NO synthase activity, increased oxidative stress, and metabolic shifts that drive cardiovascular decline. We further discuss emerging research which highlights potential interventions, including dietary nitrate supplementation, caloric restriction, and exercise, that may restore NO signaling and counteract age-related cardiovascular dysfunction. These findings underscore the growing recognition of NO as a key regulator of cardiovascular aging and a promising therapeutic target. Addressing NO-related deficits could open new avenues for preventing and treating age-associated cardiovascular diseases, reshaping strategies for promoting healthy aging and longevity.

Keywords:  Nitric oxide; Sirtuin 1 (SIRT1); cardiovascular aging; lifestyle interventions; myocardial remodeling; oxidative stress; vascular dysfunction

DOI:  https://doi.org/10.20517/jca.2025.14
bioRxiv. 2026 Mar 14. pii: 2026.03.11.710133. [Epub ahead of print]

APOE4 Accelerates Menopause-Associated Brain Metabolic Shift and Disrupts Bioenergetic Adaptation.

Tian Wang, Yuan Shang, John W McLean, Fei Yin, Roberta Diaz Brinton.

Introduction: Disruption of brain glucose and lipid metabolism contributes to Alzheimer's disease (AD) and often emerges before clinical symptoms. Women are at elevated AD risk due to menopause-associated estrogen decline, which impairs mitochondrial function and glucose metabolism. Women's risk of AD is further elevated by the APOE4 allele, the strongest genetic risk factor for late-onset AD.
Methods: To investigate the impact of APOE genotype on the menopausal metabolic transition, brain metabolomic and lipidomic profiling was conducted in humanized female APOE3/3, APOE3/4, and APOE4/4 mice across chronological and endocrinological stages of peri-to postmenopausal transition.
Results: APOE3/3 mice exhibited dynamic regulation of brain metabolic systems that supported postmenopausal bioenergetic demand. In contrast, APOE3/4 and APOE4/4 mice displayed accelerated and altered metabolic shifts, resulting in postmenopausal amino acid depletion, reduced tricarboxylic acid (TCA) cycle intermediates, lipid accumulation, and alterations in brain lipid composition. A single APOE4 allele was sufficient to impair metabolic adaptation, while APOE4 homozygosity resulted in greater severity of deficits.
Discussion: Outcomes of these analyses revealed that APOE4 accelerated menopause-related metabolic decline and compromised bioenergetic adaptation, providing a mechanistic basis for increased AD susceptibility and earlier onset in APOE4-positive women.

DOI: https://doi.org/10.64898/2026.03.11.710133
J Immunol Res. 2026 ;2026(1): e6816624

Exercise Attenuates Neuroinflammation in Chronic Restraint Stress Induced Depression Model by Downregulating GDF15 Expression.

Junrui Chen, Chunxiao Du, Jiawen Lu, Meng Liang, Miaonan Sun, Yanmin Lyu, Mengying Huang, Jixiang Sun, Yuxiang Li, Zhiding Wang, Ge Li, Gencheng Han.

  Exercise has been shown to alleviate depressive symptoms and enhance bodily functions. However, the precise mechanisms underlying its antidepressant effects remain incompletely understood. In this study, we observed that treadmill exercise may exert antidepressant effects in a chronic restraint stress (CRS) mouse model by modulating the proinflammatory Growth Differentiation Factor 15 (GDF15)-extracellular signal-regulated kinase (ERK) signaling pathway. Treadmill exercise improved cognitive behaviors in CRS mice and alleviated neuroinflammation, as evidenced by decreased expression of TNF-α, IL-1β, IL-6, and attenuated microglia activation. Intriguingly, we found that treadmill exercise inhibited the expression of GDF15, a biomarker associated with many immune disorders, which is increased following CRS. Mechanistically, treadmill exercise may attenuate neuroinflammation by suppressing GDF15-induced ERK activation. We thus identified a novel mechanism by which treadmill exercise attenuates depression. Modulation of the GDF15-ERK pathway may have therapeutic implications for depression.

Keywords:  chronic restraint stress; exercise; neuroimmune inflammation

DOI:  https://doi.org/10.1155/jimr/6816624
Neuromolecular Med. 2026 Apr 04. pii: 20. [Epub ahead of print]28(1):

SIRT1 Activators as Geroprotective Agents in Brain Aging: Mechanisms and Therapeutic Potential.

Ayman Ali Mohammed Alameen, Hayder M Al-Kuraishy, Ali I Al-Gareeb, Athanasios Alexiou, Marios Papadakis, Safaa A Faheem, Gaber El-Saber Batiha.

  The brain undergoes profound molecular and structural changes during the aging process, resulting in the development of neurodegeneration, cognitive impairment, and increased vulnerability to chronic diseases. At the cellular level, brain aging is characterized by oxidative damage, genomic instability, and chronic low-grade inflammation known as inflammaging. Central to this process is Sirtuin 1 (SIRT1), a NAD+-dependent class III histone deacetylase, known for its regulatory role in chromatin remodeling, oxidative stress responses, mitochondrial biogenesis, and neuroplasticity. Recent research has identified SIRT1 as a molecular target capable of reversing or attenuating several hallmarks of aging, particularly within the central nervous system (CNS). This narrative review critically evaluates the emerging evidence surrounding the geroprotective effects of SIRT1 activators, which exert dual actions, senomorphic and senolytic, via modulation of signaling pathways, thereby reducing neuronal senescence, enhancing autophagy, and mitigating inflammatory responses. The discussion also addresses the region-specific role of SIRT1 across the brain, particularly in the hippocampus and hypothalamus, which are essential for memory, energy homeostasis, and resilience to stress. Additionally, this review explores how SIRT1 depletion during aging contributes to the development of synaptic dysfunction, impaired cognitive function, and susceptibility to neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). The therapeutic potential of SIRT1 activators is supported by preclinical and early clinical studies, suggesting their value in preventing or delaying brain aging. Thus, SIRT1 could be a promising pharmacological target for age-associated brain disorders, warranting more robust translational studies to validate these findings in humans.

Keywords:  Brain aging; Geroprotectors; Neuroinflammation; Oxidative stress; SIRT1

DOI:  https://doi.org/10.1007/s12017-026-08923-y
J Bioenerg Biomembr. 2026 Apr 10. pii: 6. [Epub ahead of print]58(1):

Vitamin B3 rescues mitochondrial homeostasis in dexamethasone-induced skeletal muscle atrophy by reducing oxidative stress.

Akash Mitra, Samanwita Mandal, Anna Timothy Dsouza, Debajit Chaudhury, Bipasha Bose, Sudheer Shenoy P.

  Prolonged glucocorticoid exposure leads to oxidative stress, mitochondrial damage and impaired myogenesis reducing the overall health of the skeletal muscles. Dexamethasone (dex), a synthetic glucocorticoid, induces proteolysis and inflammation by disrupting cellular energetics and mitochondrial function. Vitamin B3 (vit B3), an NAD+ precursor, is known to be a natural antioxidant and anti-inflammatory compound. This study investigates the protective role of vit B3 against dex-induced skeletal muscle damage, focusing on mitochondrial homeostasis and the IKK/FoxO3a signalling axis. C2C12 myoblasts were treated with dex (200 µM) and/or vit B3 (1 mM). Oxidative stress, mitochondrial potential and DNA damage was evaluated using DCFDA, JC1, and γH2AX immunostaining, respectively. Gene expression analysis was performed to assess the mitochondrial fission/fusion and the extent of electron transport chain (ETC) gene expression. Protein expression of inflammatory (IKKα/β, NFκB) and atrophy markers were analysed using immunoblotting and flow cytometry. The extent of myogenic differentiation was evaluated using MyoD and MyHC1 immunostaining along with measurement of the morphometric parameters. Vit B3 treatment significantly enhanced C2C12 viability and reduced dex-induced ROS production while restoring Nrf2 expression. It prevented DNA damage and preserved mitochondrial membrane potential. The results also implicated increased mitochondrial fusion upon vit B3 treatment as seen by the elevated gene expression of Mfn1, Mfn2 and Opa1 and decreased fission as observed by the reduced expression of Fis1 and Drp1. The NADH levels were also seen to be rescued by vit B3 supplementation which translates to better energy production by the electron transport system. Additionally, vit B3 was observed to suppress inflammation and prevent muscle proteolysis by modulating an IKK/FoxO3a axis. Finally, vit B3 was able to improve differentiation as seen by the levels of MyoD and MyHC1 expression in the cells. Vit B3 acts in a multifaceted manner and reduces dex-induced skeletal muscle atrophy which is primarily a result of reduced oxidative stress and restored mitochondrial homeostasis. These findings highlight vit B3 as a potential therapeutic and nutritional supplement for maintaining the skeletal muscle health under myopathic conditions.

Keywords:  Mitochondrial fragmentation; Mitochondrial homeostasis; Muscle differentiation; Reactive Oxygen Species; Skeletal muscle atrophy; Vitamin B3

DOI:  https://doi.org/10.1007/s10863-026-10106-0
Cell Rep. 2026 Apr 03. pii: S2211-1247(26)00295-0. [Epub ahead of print]45(4): 117217

Exercise induces sex-specific assembly of mitochondrial supercomplexes.

Jesús R Huertas, Jerónimo Aragón-Vela, Andreas Breenfeldt Andersen, Jacob Bejder, Lars Nybo, Nikolai B Nordsborg, Andrea Rodríguez-Carrillo, José A Enriquez, Sara Cogliati, Rafael A Casuso.

  The mitochondrial respiratory complexes of the electron transport chain (ETC) form supramolecular structures known as supercomplexes (SCs) whose functions remain partially understood. An increase in carbohydrate oxidation, such as that induced by high-intensity contractions within skeletal muscle (SKM), has been proposed to promote the assembly of high molecular weight SCs (HMWSCs). Here, healthy, active young subjects (7 females and 9 males) performed a moderate- followed by a high-intensity exercise bout. We found that males increased the assembly of complex III (CIII) into SCs, particularly HMWSCs, in an intensity-dependent manner within SKM. Females showed a stable content of both HMWSCs and I+III2 SCs during exercise. In contrast, the assembly of CIV into SCs was not promoted by exercise in either sex. These findings indicate that the ETC complex organization can be modulated by exercise, and the mitochondrial supercomplex assembly in human SKM appears to be regulated in a sex-specific manner.

Keywords:  CP: metabolism; CP: molecular biology; electron transport chain; electron transport chain remodeling; high-intensity exercise; human muscle bioenergetics; lactate; mitochondrial complexes; sex-specific mitochondrial adaptation; sexual dimorphism; skeletal muscle; skeletal muscle metabolism

DOI:  https://doi.org/10.1016/j.celrep.2026.117217
Nat Commun. 2026 Apr 09.

The integrated stress response suppresses PINK1-dependent mitophagy by preserving mitochondrial import efficiency.

Mingchong Yang, Zengshuo Mo, Kelly Walsh, Wen Liu, Imane Nait Irahal, Damien Arnoult, Xiaoyan Guo.

Mitophagy is crucial for maintaining mitochondrial health, but how its levels adjust to different stress conditions remains unclear. In this study, we investigated the role of the DELE1-HRI axis of the integrated stress response (ISR) in regulating mitophagy, a key mitochondrial quality control mechanism. Our findings show that the ISR suppresses PINK1-dependent mitophagy under many mitochondrial stress conditions by maintaining mitochondrial presequence protein import, independent of ATF4 activation. Mitochondrial presequence protein import efficiency is tightly linked to the rate of protein synthesis. Without the ISR, increased protein synthesis overwhelms the mitochondrial import machineries, reducing import efficiency. This impairment can be mitigated by pharmacological attenuation of protein synthesis, such as with mTOR or general translation inhibitors. Under severe depolarizing stress, mitochondrial import is heavily impaired even with an active ISR, leading to significant PINK1 accumulation. In contrast, mild mitochondrial stress allows more efficient protein import in the presence of the ISR, resulting in lower mitophagy. Without the ISR, mitochondrial protein import becomes significantly compromised, causing PINK1 accumulation to reach the threshold level necessary to trigger mitophagy. These findings reveal a link between ISR-regulated protein synthesis, mitochondrial protein import, and mitophagy, offering potential therapeutic targets for diseases associated with mitochondrial dysfunction.

DOI: https://doi.org/10.1038/s41467-026-71630-6
Mol Nutr Food Res. 2026 Apr;70(7): e70428

Phenolics-Rich Extract From Agarwood (Aquilaria sinensis) Leaf-Tea Alleviates Hyperglycemia in Type 2 Diabetes Mellitus Mice via Modulating Lipid Metabolism and Gut Microbiota.

Yinglian Pan, Ruyan Fan, Fangliang Li, Lu Wang, Qingchun Deng.

  Agarwood (Aquilaria sinensis) leaves, as a popular substitute tea, have garneredsignificant interest due to their potential to alleviate metabolic disorders. Agarwood leaf-tea phenolic extract (ALE) has been proven to have an excellent hypoglycemic effect in vitro in our previous study. However, the alleviating effect of ALE on type 2 diabetes mellitus (T2DM) mice still remains unclear. The present study explored the effects of ALE supplementation on metabolic function and intestinal microbiota composition in T2DM. Results revealed that ALE supplementation effectively improved the typical symptoms of diabetic mice, and significantly decreased the blood glucose, insulin resistance index, and lipid accumulation in diabetic mice. In addition, ALE supplementation alleviated oxidative stress, and repaired intestinal tissue inflammation in diabetic mice. Metabolomics analysis results indicated that ALE supplementation effectively improved metabolic pathways such as phospholipid metabolism, α-linolenic acid metabolism, and folate anabolism. Gut microbiota analysis results revealed that ALE supplementation altered gut microbiota composition, increased the levels of beneficial bacteria such as Bacteroides, Oscillospiraceae, Colidextribacter, and Lachnospiraceae, and decreased the levels of harmful bacteria such as Lactobacillus, Faecalibaculum, and Turicibacter. In summary, improvements in metabolic function and gut microbiota are associated with the antidiabetic potential of ALE.

Keywords:  Aquilaria sinensis leaf‐tea; T2DM; gut microbiota; metabolomics; phenolics

DOI:  https://doi.org/10.1002/mnfr.70428
Adv Healthc Mater. 2026 Apr 11. e05925

Mitochondria-Targeted Liposomes Boost Thermogenesis for Adipose Tissue Regulation.

Shibo Tian, Hailong Xie, Qin Zhong, Chenglu Sun, Peng Yuan, Funeng Xu, Lu Lu, Jiaxue Cao, Mingzhou Li, Haohuan Li.

  Mitochondria act as central organelles regulating energy metabolism and lipogenesis in adipocytes. Mitochondrial dysfunction and oxidative stress are closely implicated in the pathogenesis of obesity. Therefore, targeting adipose mitochondrial function to reduce mitochondrial reactive oxygen (mROS) levels can enhance mitochondrial activity and promote thermogenesis, presenting a promising therapeutic strategy for obesity. In this study, we developed cationic liposomes (AE@PEP-Lip) specifically designed for adipose mitochondrial targeting. These liposomes can effectively accumulate in white adipose tissue due to their highly positively charged surface, and subsequently localize to mitochondria via the mitochondrial-targeting peptide SS-31. The SS-31 peptide efficiently scavenges mROS and synergizes with empagliflozin in AE@PEP-Lip to inhibit mitochondrial fragmentation, thereby enhancing mitochondrial respiration and thermogenic capacity. Furthermore, allicin, which is loaded into AE@PEP-Lip and released into the cytoplasm, activates the AMPK signaling pathway and upregulates uncoupling proteins, further promoting mitochondrial thermogenesis. In obese mice, treatment with AE@PEP-Lip improved mitochondrial morphology and function and induced browning characteristics. Moreover, we demonstrated the clinical application potential of AE@PEP-Lip in reducing localized fat deposition using a porcine model. Taken together, this study presents a novel and promising therapeutic platform for obesity by modulating adipose mitochondrial function.

Keywords:  adipose tissue; metabolic improvement; mitochondrial function; mitochondria‐targeted

DOI:  https://doi.org/10.1002/adhm.202505925
Geroscience. 2026 Apr 08.

Impact of miR-181a-5p and miR-1249-3p treatment on the visceral adipose tissue transcriptome of female mice.

Driele N Garcia, Bianka M Zanini, Sarah A Ashiqueali, Miguel Brieño-Enriquez, Jeffrey B Mason, Augusto Schneider, Michal M Masternak.

  MicroRNAs (miRNAs) regulate gene expression and can influence processes such as inflammation, metabolism, and aging. This study assessed the effects of miR-181a-5p and miR-1249-3p mimics on the transcriptome of visceral adipose tissue in middle-aged females mice. Mice received intraperitoneal injections of either miR-181a-5p, miR-1249-3p, or vehicle control, followed by transcriptomic and metabolic analyses. Both treatments significantly reduced fasting blood glucose levels and promoted overexpression of the respective miRNAs in adipose tissue. RNA-Seq analysis revealed that both miRNAs modulated genes involved in immune regulation, energy metabolism, and insulin signaling. miR-181a-5p predominantly upregulated immune and inflammatory pathways such as Jak-STAT and Toll-like receptor signaling, whereas miR-1249-3p downregulated metabolic pathways related to lipid oxidation and oxidative phosphorylation. Despite opposing effects, both miRNAs induced gene-expression profiles resembling those observed in long-lived, growth hormone-deficient mice, suggesting a shared role in promoting insulin sensitivity and metabolic resilience. These findings highlight miR-181a-5p and miR-1249-3p as potential therapeutic targets for improving metabolic health and delaying age-related dysfunctions in adipose tissue.

Keywords:  Adipose tissue; Female; Insulin sensitivity; Metabolism; MiRNA

DOI:  https://doi.org/10.1007/s11357-026-02247-2
Ageing Res Rev. 2026 Apr 02. pii: S1568-1637(26)00115-7. [Epub ahead of print]118 103123

Sex differences in response to longevity interventions.

Kaitlyn H Hajdarovic, Nicole C Riddle, Ashley E Webb.

  Interventions to extend lifespan and healthspan are of major interest, but such interventions may affect male and female organisms differently. Whether this is due sex-specific differences in baseline lifespan, or differences in sexually dimorphic characteristics such as body size, adiposity, metabolism, or even gonadal hormone or chromosome status remains unknown. Here we discuss the literature on how males and females respond differently to various types of interventions known to extend lifespan and explore possible underlying mechanisms. Ultimately, understanding sex as a biological variable in the context of aging may reveal sex-specific strategies to improve healthspan and treat age-related disease.

Keywords:  Aging; Healthspan; Lifespan; Longevity; Sex; Sexual dimorphism

DOI:  https://doi.org/10.1016/j.arr.2026.103123
bioRxiv. 2026 Mar 30. pii: 2026.03.27.714765. [Epub ahead of print]

Carnitine deficiency alters fuel metabolism and voluntary wheel running in mice.

Meagan S Kingren, Daniel G Sadler, Elijah Bolin, Izak Harville, James Sikes, Renny Lan, Elisabet Børsheim, Craig Porter.

Background: Carnitine plays an obligatory role in energetics owing to its role in the translocation of long-chain fatty acids into the mitochondrion for oxidation. Here, we determined the metabolic and behavioral consequences of systemic carnitine deficiency (SCD) in mice.
Methods: Female C57BL/6J mice were randomized to receive normal drinking water (control, n = 8) or drinking water supplemented with mildronate 4g.L-1 (mildronate, n = 8) for 21 days. Body composition was assessed at baseline and post treatment. Metabolic and behavioral phenotyping was performed continuously over 72 hours following 14 days of control or mildronate treatment. Stable isotope were used to assess whole-body substrate oxidation. Carnitine subfractions were quantified in skeletal muscle and liver, as was mitochondrial respiratory function. Liver and muscle samples also underwent proteomic analysis.
Results: Mildronate treatment depleted total carnitine in muscle and liver by ∼97% ( P < 0.001) and ∼90% ( P < 0.001), respectively. Carnitine depletion was accompanied by lower total energy expenditure ( P = 0.01), attributable to lower voluntary wheel running ( P = 0.01). Oxidation rates of palmitate ( P < 0.01) but not octanoate were lower whereas rates of glucose oxidation were greater in carnitine depleted mice ( P < 0.01). Mitochondrial respiratory capacity was unaltered by carnitine deficiency. Carnitine deficiency remodeled muscle and liver proteomes to support lipid oxidation and energy production.
Summary: In mice, carnitine deficiency is characterized by decreased long-chain fatty acid oxidation despite preserved mitochondrial respiratory capacity. Carnitine deficiency resulted in lower voluntary exercise and a concomitant reduction in energy expenditure.

DOI: https://doi.org/10.64898/2026.03.27.714765
Clin Endocrinol (Oxf). 2026 Apr 07.

Metabolic Phenotype Predicts Biochemical Response to Inositol Supplementation in Polycystic Ovary Syndrome: A Systematic Review and Meta-Analysis.

Daniele Tienforti, Gennaro Puocci, Claudia Venditti, Valentina Gizzi, Carlo Pisanò, Elisa Cocci, Elisabetta Perfetto, Francesco D'Alessandro, Luca Spagnolo, Marco Giorgio Baroni, Arcangelo Barbonetti.

   OBJECTIVE: To evaluate the effect of inositol supplementation on biochemical hyperandrogenism in women with polycystic ovary syndrome (PCOS) and to explore whether metabolic phenotype modifies the endocrine response.
DESIGN: Systematic review and meta-analysis of randomized controlled trials conducted in accordance with PRISMA guidelines.
PATIENTS: Women diagnosed with PCOS according to established criteria (NIH, Rotterdam, or AE-PCOS). Nine eligible trials comprising a total of 440 participants were included.
MEASUREMENTS: Primary outcomes were serum total testosterone (TT), calculated free testosterone (cFT), free androgen index (FAI), and sex hormone-binding globulin (SHBG). Prespecified subgroup analyses explored differences according to body mass index (BMI) and insulin resistance (HOMA-IR).
RESULTS: Inositol supplementation was associated with significant reductions in TT (SMD -1.30; 95% CI -2.17 to -0.42), cFT, and FAI, together with an increase in SHBG. Substantial heterogeneity was observed for several outcomes. In subgroup analyses, the largest and most consistent reduction in TT was observed among normal-weight women (BMI < 25 kg/m²) (SMD -2.97; 95% CI -3.78 to -2.16), with minimal heterogeneity (I² = 9%). No significant improvements were detected in overweight or obese women, nor in women with insulin resistance when considered independently of BMI. These subgroup findings should be interpreted as exploratory.
CONCLUSIONS: Inositol supplementation is associated with improvements in biochemical hyperandrogenism in women with PCOS, with evidence of phenotype-dependent variability. The most consistent biochemical response was observed in normal-weight individuals. These findings support a metabolically informed, hypothesis-generating framework and highlight the need for adequately powered, phenotype-stratified trials incorporating clinically meaningful outcomes, including standardized measures of hirsutism, ovulatory function, and patient-reported endpoints.

Keywords:  D‐chiro‐Inositol; hyperandrogenism; inositol; insulin resistance; myo‐inositol; polycystic ovary syndrome; precision medicine

DOI:  https://doi.org/10.1111/cen.70140
J Biochem Mol Toxicol. 2026 Apr;40(4): e70830

From Defence to Dysfunction: The Dual Role of Autophagy and Mitophagy in Cardiomyopathy.

Nandini Dubey, Gauri Chaturvedi, Pranav Panchbhai, Satnam Singh, Ahsas Goyal, Nirmal Singh, Vishal Kumar Vishwakarma, Neeraj Parakh, Lakshmy Ramakrishnan, Harlokesh Narayan Yadav.

  Cardiomyopathy is a disease unique to the heart muscle that increases a patient's risk of death due to heart failure, contrary to vascular conditions. Cellular powerhouses called mitochondria produce oxygen species that are reactive, that may damage both the mitochondria as well as the heart muscle if they are not managed. They also provide energy for contractions in the heart. Maintaining proper heart function both at base and in reaction to various stress and illness circumstances depends on autophagy as well as mitochondrial autophagy, which eliminates damaged mitochondria. Understanding the pathogenesis of heart diseases, which includes a wide spectrum of cardiovascular problems connected to related cardiomyopathies, is still hampered by autophagy and mitophagy. Additionally, heart failure continues to be a primary source of increased morbidity among people with cardiomyopathy, despite notable advances in lowering death rates from cardiovascular diseases (CVDs). Due to their role in the development of cardiovascular conditions, these cellular processes are appealing targets for diagnosis and therapy. They are crucial for preserving cellular equilibrium and eliminating damaged or malfunctioning components. Further, cardiomyopathies remain a major concern despite the availability of several traditional diagnostic and treatment approaches. Thus, we are going to explore the possible autophagy and mitophagy in the development and progression of cardiomyopathy and provide an overview of current research in this area in this review.

Keywords:  autophagy; cardiomyopathy; heart failure; mitochondria; mitophagy

DOI:  https://doi.org/10.1002/jbt.70830
Front Endocrinol (Lausanne). 2026 ;17 1768772

Estrogen signaling processes in fibroblasts: a scoping review.

Neena Roy, Livio Casarini, Darya Smetanina, Shamsa Al Awar, Kornelia Zaręba.

  Fibroblasts are a heterogeneous cell population with distinct functions, known to respond to estrogens through nuclear estrogen receptor alpha and beta (ERα, ERβ), and the membrane G protein-coupled estrogen receptor (GPER). In this scoping review, we systematically mapped the current evidence on the contribution of estrogen, phytoestrogens, and selective estrogen receptor modulators (SERMs) on estrogen signaling in fibroblasts. A systematic search across PubMed, Scopus and EMBASE was conducted, followed by screening of titles/abstracts, and full text in Covidence, resulting in 67 eligible studies. Our findings reveal that fibroblasts respond to estradiol (E2), phytoestrogens, and SERMs, activating both genomic and non-genomic responses through ERα, ERβ and GPER. These responses contribute to anti-fibrosis, wound healing, anti-inflammatory, and protective effects across diverse fibroblast models. In contrast, in cancer-associated fibroblasts, these ligands can promote cancer in a paracrine manner, emphasizing the role of the tumor microenvironment in cancer progression. However, significant gaps including small sample sizes, high ligand concentrations, lack of mechanistic detail and limited investigation of sex-specific fibroblast responses remain. Addressing these gaps by standardized experimental designs, physiologically relevant models, clearer distinction of receptor-specific pathways and sex-specific analyses in future research will advance the understanding of estrogen-mediated fibroblast signaling and aid in the development of novel therapeutic targets for estrogen-related disorders.

Keywords:  GPER; SERM; estrogen pathway; estrogen receptor; estrogen signaling; fibroblasts; phytoestrogen

DOI:  https://doi.org/10.3389/fendo.2026.1768772
CPT Pharmacometrics Syst Pharmacol. 2026 Apr;15(4): e70243

The Role of Estradiol in Oxidative Stress in Health and Cystathionine ß-Synthase Deficiency: A Mechanistic Model.

Allison Cruikshank, H Frederik Nijhout, Michael C Reed.

  Oxidative stress occurs when there is an imbalance between oxidants and antioxidants, leading to the accumulation of reactive oxygen species (ROS). Excessive ROS can damage lipids, proteins, and DNA, contributing to cellular dysfunction and disease. Interestingly, premenopausal females tend to have lower levels of oxidative stress and higher concentrations of certain antioxidants, such as glutathione (GSH), compared to males and postmenopausal females. These differences point to the important role of sex hormones in regulating oxidative stress and its effects on the body. Yet, clinical and experimental studies report conflicting effects of estradiol, particularly across the menstrual cycle in premenopausal females and in estradiol supplementation in postmenopausal females. Here, we present a mechanistic mathematical model of hydrogen peroxide (H2O2), a key ROS, that explicitly incorporates estradiol and progesterone regulation of key enzymes. Using this model, we elucidate the mechanisms underlying females' lower oxidative stress and provide an explanation for the seemingly contradictory clinical observations at both steady state and during the menstrual cycle. We further apply the model to examine sex differences in cystathionine β-synthase deficiency, explaining the attenuation of sex differences in key metabolites in the pathway. By connecting clinical observations with mathematical modeling, this work provides insights into the underlying mechanisms and paves the way for sex- and menopausal status-specific approaches in medicine and drug development.

Keywords:  CBS deficiency; estrogen supplementation; oxidative stress; sex differences

DOI:  https://doi.org/10.1002/psp4.70243
Res Sq. 2026 Mar 30. pii: rs.3.rs-9237764. [Epub ahead of print]

Metabolic Adaptations to Caloric Restriction: Time- and Group-Dependent Metabolomic Signatures from the CALERIE™ Trial.

Melissa C Orenduff, Emily K Woolf, Ruiqi Zhang, Daniel W Belsky, Sai Krupa Das, Waylon Hastings, Justine M Mucinski, Susan B Racette, Leanne M Redman, Reem Waziry, William E Kraus, Carl F Pieper, Kim M Huffman.

Background : Caloric restriction (CR) improves markers of biological aging, yet long-term effects on the human metabolome remain unclear. Objective: This study examined the effects of CR (2 years) in healthy adults without obesity on circulating metabolites linked to aging and metabolic adaptations. Methods: Untargeted metabolomics was performed using fasted plasma samples collected at baseline, 12, and 24 months (BL, 12M, 24M) from CALERIE™ participants randomized to CR or ad libitum (AL) control. A total of 864 known metabolites were identified and grouped into nine biologically coherent super pathways to support pathway‑level interpretation (amino acid, peptide, carbohydrate, energy, lipid, nucleotide, cofactors and vitamins, xenobiotics, and partially characterized molecules). Principal component analysis (PCA) summarized metabolite variation, and linear mixed models assessed intervention effects on each PC in group-by-time interactions. Results: Three principal components showed significant group‑by‑time interactions: PC2 (carbohydrate), PC5 (partially characterized molecules), and PC4 (lipid). Carbohydrate (PC2) and partially characterized metabolites (PC5) decreased from baseline to 12M in both groups; from 12M to 24M, levels stabilized in CR but increased in AL for PC2, while PC5 continued to decline in AL and increased in CR. Lipid metabolites (PC4) decreased in CR and increased in AL at 12M, with the pattern reversing from 12M to 24M. Key contributors included malto‑saccharides and related carbohydrate intermediates for PC2, glutamine degradants and lactone sulfates for PC5, and sphingolipids for PC4. Conclusion: Calorie restriction produced distinct, time‑dependent shifts in carbohydrate and lipid metabolism, with early reductions during the weight‑loss phase followed by stabilization or compensatory responses during weight maintenance. These dynamic metabolic changes may relate to inflammation‑linked mechanisms. Further work is needed to distinguish CR‑specific adaptations from dietary influences and to clarify the functional significance of these metabolic responses for aging and long‑term metabolic health.

DOI: https://doi.org/10.21203/rs.3.rs-9237764/v1
Aging Cell. 2026 Apr;25(4): e70468

Double-Pronged NAD Preservation: Delaying Cellular Senescence and Initiating Musculoskeletal Regeneration.

Jianfeng Yu, Mingzhuang Hou, Yaoge Deng, Chenqi Yu, Yang Liu, Kang Kang, Xiaowei Xia, Xiaoping Li, Huilin Yang, Dinghua Jiang, Wu Xu, Yijian Zhang, Xuesong Zhu.

  In the context of population aging, musculoskeletal fitness has emerged as a cornerstone of overall well-being and injury prevention, relying on the coordinated function of cartilage, bone, and muscle. Drawing on the principle of "increasing income and reducing expenditure," we propose a combinatorial formulation consisting of the nicotinamide adenine dinucleotide (NAD) precursor nicotinamide mononucleotide (NMN) and the NAD+-consuming enzyme inhibitor apigenin (API), hereafter referred to as the "N + A" regimen, to enhance NAD+ reserves. Our results revealed that the N + A formulation alleviated cellular senescence, thereby promoting the differentiation of skeletal precursor cells into chondrocytes, osteoblasts, and myocytes for the reconstruction of the musculoskeletal system. Oral administration of the N + A formulation alleviated cartilage degeneration, bone loss, and muscle atrophy; additionally, it enhanced exercise capacity in aged mice. Mechanistically, the N + A strategy preserves NAD+ levels, which are subsequently utilized by mitochondrial sirtuin 3 (SIRT3) to promote deacetylation modifications and alleviate the senescent phenotype. Moreover, oral administration of N + A indirectly enhanced the synthesis of the metabolite phytosphingosine (PHS) by the intestinal microbiota members Coriobacteriaceae_UCG-002 and Ruminococcus, thereby alleviating age-related degeneration. In summary, our findings demonstrate that enhancing the NAD+ reservoir represents a promising strategy for promoting musculoskeletal regeneration, and we developed a rational combinatorial regimen with potential for clinical translation.

Keywords:  apigenin; cellular senescence; musculoskeletal disorders; nicotinamide adenine dinucleotide; nicotinamide mononucleotide; phytosphingosine

DOI:  https://doi.org/10.1111/acel.70468
Transl Psychiatry. 2026 Apr 06.

Brain energetic landscapes shape state dysregulation in major depressive disorder: a morphological network controllability perspective.

Jinpeng Niu, Jie Xia, Qingjin Liu, Yaohui He, Wei Li, Kangjia Chen, Xi Zhang, Jiang Qiu, Huafu Chen, Jiao Li, Wei Liao.

Aberrant dynamic shifts in brain states are a hallmark of cognitive and behavioral dysfunctions in major depressive disorder (MDD), yet the underlying mechanisms of these disturbances remain elusive. Leveraging network control theory of morphological networks, we characterized aberrant brain dynamics and energy deficits of MDD patients in two independent cohorts. MDD patients exhibited reduced dynamic stability, characterized by elevated intra-state transitions and diminished inter-state transitions, which were associated with impaired control energy. Region-specific deficits of energy regulation capacity were observed in key nodes of the default mode and limbic networks, including the posterior cingulate cortex and temporal pole, which correlated with cognition and clinical symptoms in MDD patients. MDD-related energy inefficiency was related to multiscale energy architectures at cellular, molecular, and biological levels, including mitochondrial morphologies and functions, energy metabolism pathways, and brain metabolic patterns. Additionally, we demonstrated an association between energy demands and cortical dynamics, indicating a disrupted energy-dependent neurophysiological activity in MDD patients. Together, these results identified the energetic fundamentals underlying pathological brain-state transitions in MDD patients. Identifying energy-vulnerable nodes from a controllability perspective may therefore provide valuable targets for restoring normative neural dynamics in MDD.

DOI: https://doi.org/10.1038/s41398-026-04025-2