bims-mistre Biomed News
on Mito stress
Issue of 2026–02–22
seventeen papers selected by
Ellen Siobhan Mitchell, MitoQ
  1. Reduced Versus Oxidized NAD+ Precursors Drive Distinct Transcriptomic, Proteomic, and Metabolic Profiles in Hepatocytes.
  2. Growth differentiation factor 15 mitigates lipotoxic steatosis by preserving mitochondrial morphodynamics and augmenting fatty acid oxidation in hepatocytes and liver organoids.
  3. Redox therapy for neuropsychiatric disorders: Molecular mechanisms and biomarker development.
  4. Pro-longevity compounds extend Caenorhabditis elegans male lifespan and reproductive healthspan.
  5. Peucedanum japonicum Thunb. ameliorates age-related muscle loss by improving mitochondrial function in aged mice.
  6. Age-related mitochondrial energy metabolism reprogramming occurs in granulosa cells during ovarian aging.
  7. Extracellular Vesicle-Derived Mitochondrial Genes as Potential Biomarkers for Brain Aging in Human.
  8. Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
  9. Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.
  10. Effects of astaxanthin supplementation on exercise-induced oxidative stress: a systematic review and meta-analysis of randomized controlled trials.
  11. Striatal Dopamine and Skeletal Muscle Energy Metabolism in Older Adults.
  12. Sex as a Moderator of the Association between Cardiorespiratory Fitness and Depressive Symptoms in Older Adults.
  13. Benefits of Oral Nitrite Supplementation on Mitochondrial Respiration and Physical Function In Older Adults.
  14. Eicosapentaenoic Acid Attenuates Type 2 Diabetes Mellitus-Related Sarcopenia in Mice and Its Potential Mechanisms.
  15. Time since menopause and a circulating metabolomic signature for sarcopenia risk: Data from 68,064 women from the UK Biobank.
  16. Molecular pathways linking chronic psychological stress to accelerated aging: mechanisms and interventions.
  17. Antioxidant Delivery Revisited: The Promise of Nanostructured Lipid Carriers.
  1. FASEB J. 2026 Feb 28. 40(4): e71582
    Reduced Versus Oxidized NAD+ Precursors Drive Distinct Transcriptomic, Proteomic, and Metabolic Profiles in Hepatocytes.
    Kasper T Vinten, Bauke V Schomakers, Simone Denis, Michel van Weeghel, Aldo Jongejan, Rob Ofman, Sander R Piersma, Connie R Jimenez, Georges E Janssens, Rubén Zapata-Pérez, Riekelt H Houtkooper.
      Nicotinamide adenine dinucleotide (NAD+) is a vital molecule, serving as a redox cofactor and the limiting substrate for numerous enzymes. NAD+ decline is a key feature of aging, while supplementation with NAD+ precursors can efficiently counteract aging traits and prevent age-associated conditions in preclinical models. However, clinical translation remains challenging, likely due to the limited NAD+ boosting capacity of classical precursors, such as nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). This has brought attention to their reduced forms, reduced NMN (NMNH) and reduced NR (NRH), which are more potent NAD+ boosters but remain poorly characterized. Here, we performed a comprehensive comparative analysis using RNA sequencing, proteomics, and metabolomics on cultured murine hepatocytes treated with NMN, NMNH, NR, or NRH. Global metabolic profiling revealed that NRH and NMNH induced substantially broader metabolic alterations than NR and NMN, with NRH uniquely suppressing metabolites involved in energy metabolism. The pronounced metabolic effects were reflected at a transcriptional level, with reduced precursors triggering a significantly higher number of differentially expressed genes than oxidized ones. Shared differentially expressed genes between NMNH and NRH revealed upregulation of stress-related glutathione-S-transferases (Gsts) which furthermore were reflected in our proteomic profiling. However, the upregulation of Gsts did not cause a depletion of glutathione or oxiglutathione, suggesting a pseudo-stress response to reduced NAD+ precursors. Together, our data demonstrate that reduced NAD+ precursors are unique and distinct from the market-available NAD+ precursors NR and NMN, not only as more potent NAD+ boosters, but also as compounds influencing a broader range of cellular processes.
    Keywords:  NAD+; NAD+ precursors; comparative analysis; hepatocytes
    DOI:  https://doi.org/10.1096/fj.202501925R
  2. Diabetes Obes Metab. 2026 Feb 19.
    Growth differentiation factor 15 mitigates lipotoxic steatosis by preserving mitochondrial morphodynamics and augmenting fatty acid oxidation in hepatocytes and liver organoids.
    Jia Li, Qi Zhou, Mengmeng Xia, Yakun Li, Junyu Wang, Manon Buist-Homan, Vincent E de Meijer, Hans Blokzijl, Klaas Nico Faber, Han Moshage.
       AIMS: Growth differentiation factor 15 (GDF15) has emerged as a promising metabolic regulator with hepatoprotective properties in metabolic dysfunction-associated steatotic liver disease (MASLD), yet its underlying mechanisms remain elusive. Given that mitochondria are the primary site of fatty acid oxidation (FAO) and that mitochondrial morphodynamics are critical for normal hepatic lipid metabolism, we investigated how GDF15 regulates hepatic lipid homeostasis through mitochondrial dynamics.
    MATERIALS AND METHODS: We established cellular steatosis models using primary rat hepatocytes exposed to lipotoxic palmitate (PA) or non-lipotoxic free fatty acid mixture (FFA, oleate: palmitate = 2: 1). Following GDF15 administration, we quantified lipid droplet content, expression of lipid metabolism genes, mitochondrial fatty acid translocation, and mitochondrial morphodynamics and function. The mechanistic role of ERK1/2 signalling was assessed through pharmacological inhibition. These findings were subsequently validated in adult progenitor cell-derived human liver organoids.
    RESULTS: GDF15 significantly mitigated both PA- and FFA-induced lipid accumulation by upregulating key FAO genes and down regulating lipid synthesis genes. Importantly, GDF15 corrected PA-induced mitochondrial fusion-fission imbalance by increasing mitochondrial fusion proteins MFN1 and OPA1 while modulating the activation of fission regulator DRP1. GDF15 enhanced fatty acid translocation into mitochondria and improved FAO. Mechanistically, GDF15 exerted these effects partially through inhibition of the ERK1/2 signalling pathway. Human liver organoid models further corroborated this protective mechanism of GDF15 against hepatic steatosis.
    CONCLUSIONS: Our study reveals that, specifically under lipotoxic conditions, GDF15 alleviates hepatocyte steatosis by preserving mitochondrial morphodynamics homeostasis and enhancing mitochondrial FAO capacity via ERK1/2 inhibition. These condition-specific mechanisms provide critical insights into GDF15's hepatoprotective effects and support its further investigation as a potential therapeutic target for MASLD.
    Keywords:  GDF15; MASLD; lipid metabolism; mitochondrial morphodynamics
    DOI:  https://doi.org/10.1111/dom.70561
  3. Sci Adv. 2026 Feb 20. 12(8): eaea9014
    Redox therapy for neuropsychiatric disorders: Molecular mechanisms and biomarker development.
    Kyle W Cuklanz, Abigail Stein, Virginie-Anne Chouinard, Dost Ongur, Fei Du.
      Redox dysregulation, characterized by an imbalance in the NAD+ [nicotinamide adenine dinucleotide (oxidized form)]/NADH (reduced form of NAD+) ratio, is implicated in neurodegenerative and psychiatric disorders such as Alzheimer's disease and schizophrenia. This imbalance contributes to mitochondrial dysregulation, oxidative stress, and inflammation. Despite promising preclinical studies supporting therapeutic strategies aimed at restoring redox balance and thereby rescuing brain bioenergetic deficits, clinical outcomes and efficacy remain limited. Progress has been hindered by the incomplete understanding of NAD+ subcellular cycling, as well as a lack of in vivo biomarkers measuring target engagement of redox status and mitochondrial function. Thus, this review examines molecular mechanisms of NAD (nicotinamide adenine dinucleotide)-related bioenergetic deficits, current and emerging NAD-targeted therapies, and recent advances in the development of neuroimaging biomarkers, emphasizing personalized and mechanism-driven approaches.
    DOI:  https://doi.org/10.1126/sciadv.aea9014
  4. Geroscience. 2026 Feb 17.
    Pro-longevity compounds extend Caenorhabditis elegans male lifespan and reproductive healthspan.
    Rose S Al-Saadi, Patrick C Phillips.
      Sex differences in aging are robust and ubiquitous. Demographic differences in aging generated by sex have long been recognized, but the underlying biological basis for these differences and the potential for sex-specific interventions remain understudied. To explore sex differences in the response to pro-longevity interventions, we utilized the C. elegans aging model and asked whether male lifespan and reproductive healthspan can be extended via compounds known to have pro-longevity effects in hermaphrodites. We tested seven different compounds at two concentrations each and found that lifespan was extended under all tested conditions. However, reproductive healthspan measured by mating success in late life improved under only two tested conditions, sulforaphane and metformin. These results demonstrate that lifespan and healthspan can be decoupled in C. elegans males and offer a new framework for screening pro-longevity compounds and for studying sex differences in aging in a classical aging model.
    Keywords:   C. elegans ; Healthspan; Pro-longevity interventions; Sex differences
    DOI:  https://doi.org/10.1007/s11357-026-02144-8
  5. Geroscience. 2026 Feb 17.
    Peucedanum japonicum Thunb. ameliorates age-related muscle loss by improving mitochondrial function in aged mice.
    Young In Kim, Young-Soo Kim, Chang Hwa Jung, Jiyun Ahn.
      Peucedanum japonicum Thunb. (PJ), also known as costal hog fennel, is an edible medicinal plant recognized for its potential health benefits. We previously demonstrated the protective effects of PJ against muscle atrophy in young mice. In the present study, we investigated whether PJ also inhibits age-related muscle loss in aged mice. PJ treatment of primary myoblasts derived from aged mice attenuated myotube diameter reduction, suppressed the expression of atrogenes, and prevented the fast-to-slow myosin heavy chain (MHC) fiber type transition. Additionally, PJ improved mitochondrial respiratory capacity, accompanied by increased PGC1α expression and phosphorylation. Aged mice (20 months old) were fed diets supplemented with 0.1% or 0.2% PJ for eight weeks. PJ supplementation enhanced muscle strength and physicalrformance parameters, including treadmill endurance and stride length. Increases in lean body mass, muscle weight, cross-sectional area (CSA), and the ratio of MHCII to MHCI fibers were observed. These improvements were associated with reduced ubiquitin-dependent protein degradation and the downregulation of atrogenes. Furthermore, PJ supplementation promoted mitochondrial activity via PGC1α and stimulated mitochondrial biogenesis through the Nrf1-Tfam pathway. 4-Caffeoylquinic acid (4-CQA), a major bioactive compound in PJ, attenuated myotube atrophy and enhanced mitochondrial respiration in aged myoblasts. These findings suggested that PJ, along with its active compound 4-CQA, has therapeutic potential for combating age-related muscle loss.
    Keywords:   Peucedanum japonicum Thunb.; Aging; Mitochondrial dysfunction; Proteostasis; Sarcopenia
    DOI:  https://doi.org/10.1007/s11357-026-02123-z
  6. Front Endocrinol (Lausanne). 2026 ;17 1726339
    Age-related mitochondrial energy metabolism reprogramming occurs in granulosa cells during ovarian aging.
    Mengyu Shi, Zhicheng Jia, Xinxin Yang, Wenlong Qi, Xinwei Sun, Yongqian Li, Peixuan Wang, Ying Guo.
       Objective: Ovarian aging is an inevitable age-associated biological phenomenon.Enhancing clinical pregnancy outcomes in women with advanced maternal age (AMA) has emerged as a critical research priority in reproductive medicine. The current study seeks to unravel the mechanism governing mitochondrial energy metabolism reprogramming in granulosa cells (GCs) during age-associated ovarian aging.
    Methods: We conducted an age-stratified prospective observational study involving GC samples from 10 young infertile women (young group: 21-34 years) and 10 infertile women with AMA (AMA group: 35-42 years), all undergoing in vitro fertilization-embryo transfer (IVF-ET). Participants were recruited from November 2023 to November 2024. Additionally, an in vitro oxidative stress-induced senescence model was established using hydrogen peroxide (H2O2)-treated human ovarian granulosa-like tumor cell line (KGN cells) to further investigate metabolic disturbances and mitochondrial reactive oxygen species (mtROS) levels in senescent GCs.
    Results: High-resolution targeted metabolomics revealed 25 statistically significant metabolite alterations in ovarian GCs, indicating profound dysregulation of core energy metabolism pathways-particularly oxidative phosphorylation (OXPHOS), glycolysis, and the tricarboxylic acid (TCA) cycle. Compared to the young group, the AMA group exhibited upregulated glycolytic metabolites alongside downregulated OXPHOS and TCA cycle intermediates. These findings were further validated in an H2O2-induced KGN cells senescence model, where treated cells demonstrated: (1) increased senescence-associated β-galactosidase (SA-β-gal) activity, (2) elevated extracellular acidification rate (ECAR) and lactate (Lac) production, (3) reduced oxygen consumption rate (OCR), (4) depleted glucose and pyruvate(Pyr) pools, and (5) heightened mtROS generation relative to control group.
    Conclusions: Collectively, our research demonstrates that GCs undergo mitochondrial energy metabolism reprogramming, characterized by a metabolic shift from OXPHOS to glycolysis, during ovarian aging. These observations suggest that age-associated glycometabolic perturbations may represent a novel therapeutic target for infertility in women with AMA.
    Keywords:  KGN cells; female infertility; granulosa cells; mitochondrial energy metabolism reprogramming; ovarian aging
    DOI:  https://doi.org/10.3389/fendo.2026.1726339
  7. J Gerontol A Biol Sci Med Sci. 2026 Feb 17. pii: glag044. [Epub ahead of print]
    Extracellular Vesicle-Derived Mitochondrial Genes as Potential Biomarkers for Brain Aging in Human.
    Qian Yu, Shuyi Yu, Hang Chen, Zhikang Cui, Qian Cheng, Yan Jin, Shuai Zong, Yunshan Wang, Ming Li, Zhiming Lu.
      Aging significantly impacts brain function, and identifying reliable biomarkers for early detection of age-related neurodegeneration is crucial for improving diagnosis and treatment outcomes. This proof-of-principle study aims to evaluate the abundance of mitochondrial DNA (mtDNA) targets within plasma-derived extracellular vesicles (EVs) and to investigate whether they correlate with established biomarkers of brain aging, independent of chronological age and renal function. mtDNA copy number was quantified using absolute quantitative PCR (qPCR). Brain aging biomarkers were measured by ELISA. Multivariable regression analysis was performed to examine the associations between EVs mitochondrial genes and aging biomarkers. A multi-biomarker model was developed to assess the performance of combined biomarkers in distinguishing between age groups. We observed that EV mitochondrial gene levels were significantly increased with age (P < 0.001). Levels of neurofilament light chain (NfL), amyloid-beta (Aβ42 and Aβ40), also showed significant age-related increases (P < 0.001). A multi-biomarker model combining EVs mitochondrial genes and brain aging biomarkers showed the optimal performance in distinguishing older adults from younger individuals, with an area under the ROC curve (AUC) significantly higher than that of any single biomarker (P < 0.01). These findings collectively indicate that EV-derived mitochondrial genes, in combination with other biomarkers like NfL, hold great potential as a non-invasive tool for early detection and monitoring of brain aging and neurodegenerative diseases.
    Keywords:  Aging; Biomarker; Extracellular vesicles; Mitochondrial Genes
    DOI:  https://doi.org/10.1093/gerona/glag044
  8. Cell Metab. 2026 Feb 17. pii: S1550-4131(26)00012-4. [Epub ahead of print]
    Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
    Iñigo Chivite, Erika Monelli, Margalida Munar-Gelabert, Alicia G Gómez-Valadés, Abdiel Alvarado-Diaz, Macarena Pozo, Luis Varela, Sara Ramírez, Roberta Haddad-Tóvolli, Miriam Toledo, Júlia Fos-Domènech, Francisco Díaz-Castro, Iasim Tahiri, Pau García-Ramón, Mariana Ferreira, Chloé van Gelder, Anne Abot, Óscar Osorio-Conles, José Antonio Valer, Arnaud Obri, Maria Milà-Guasch, Jorge Alvarez Luis, Pilar Villacampa, Elena Eyre, Jordi Altirriba, Sabrina Genßler, Markus Haake, Christine Schuberth-Wagner, Xavier Remesar, Antonio Zorzano, Pablo M Garcia-Rovés, Francesc Ventura, Josep Vidal, Claude Knauf, Rubén Nogueiras, Tamas L Horvath, Katrien De Bock, Mariona Graupera, Marc Claret.
      Endothelial cells (ECs) are key metabolic gatekeepers, yet their role in metabolic health remains unclear. Given their central involvement in energy metabolism, mitochondria are ideally positioned to enable ECs to adapt to ever-changing metabolic requirements. Here, we explore the hypothesis that mitochondrial dynamics proteins in ECs influence whole-body metabolic status. Genetic deficiency of Mfn2 in ECs (Mfn2iΔEC), but not of Mfn1iΔEC, induces a mitohormetic response in the adipose vasculature, enhancing antioxidant defenses, mitochondrial fitness, and lipid oxidation, ultimately improving metabolic outcomes. Cultured ECs secrete the mitokine growth differentiation factor 15 (GDF15) via a forkhead box O1 (FOXO1)-dependent axis, a response also observed under stress conditions in vivo. Notably, Mfn2iΔEC mice exhibited elevated endothelial and circulating GDF15 levels, and neutralization of GDF15 partly attenuated their metabolic benefits. Consistent with mitohormetic activation, Mfn2iΔEC mice showed protection against diet-induced obesity and delayed age-related decline. Hence, vascular mitohormetic adaptations emerge as a novel mechanism promoting systemic metabolic health.
    Keywords:  GDF15; aging; diabetes; endothelial cells; mitochondria; mitofusin; mitohormesis; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2026.01.012
  9. Front Aging Neurosci. 2026 ;18 1689139
    Changes in the brain [NAD+]/[NADH] and [NADPH]/[NADP+] with aging and anti-aging dietary restriction.
    Leah E Jamerson, Tara D Bradshaw, Patrick C Bradshaw.
      Changes in brain [NADPH]/[NADP+] and [NAD+]/[NADH] may contribute to aging. Anti-aging dietary restriction (DR) and intermittent fasting (IF) alter redox states that may contribute to their longevity effects. Pyruvate/lactate and acetoacetate/beta-hydroxybutyrate are indicators of the cytoplasmic and mitochondrial [NAD+]/[NADH], respectively, while the malate/pyruvate and isocitrate/alpha-ketoglutarate are indicators of the cytoplasmic [NADPH]/[NADP+]. Using these metabolite-pair ratios as redox indicators, the C57BL/6J mouse brain showed opposite redox changes with aging to the C57BL/6N mouse brain and human brain in the cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+]. Fasting caused universal reductive shifts in the brain cytoplasmic [NAD+]/[NADH] and [NADPH]/[NADP+] and mitochondrial [NAD+]/[NADH]. The reductive shift in the cytoplasmic [NAD+]/[NADH] with fasting was opposite to that occurring with anti-aging ketone ester supplementation or ketogenic diet, which have been shown to cause an oxidative shift of the cytoplasmic [NAD+]/[NADH], but a reductive shift of the cerebral cortical cytoplasmic [NADPH]/[NADP+]. Several pathways that influence redox metabolism and aging are discussed, including fatty acid and cholesterol synthesis, the citric acid cycle, fatty acid beta-oxidation, glutaminolysis, the malate-aspartate shuttle, the glycerol-3-phosphate shuttle, the citrate-pyruvate shuttle, and the citrate-alpha-ketoglutarate shuttle. Brain proteome, brain single-cell RNA-Seq, and brain-region-specific bulk RNA-Seq data sets of aging and DR were examined, focusing on the pathways listed above to determine how they might contribute to the redox changes. Intermittent fasting has been shown to induce cyclic metabolic switching that contributes to neuroprotection and other health benefits resulting in delayed aging, while cyclic reductive redox shifts, especially in mitochondria, may be a driver of the beneficial effects.
    Keywords:  NAD+; NADPH; aging; astrocyte; brain; dietary restriction; fasting; redox
    DOI:  https://doi.org/10.3389/fnagi.2026.1689139
  10. 3 Biotech. 2026 Mar;16(3): 98
    Effects of astaxanthin supplementation on exercise-induced oxidative stress: a systematic review and meta-analysis of randomized controlled trials.
    Ting You, Kejia Peng, Kai Zhao, Shuning Liu, Fujian Sun, Bizhu Yu, Yue Dou, Junhua Tang, Wei Jiang, Chang Liu.
      Astaxanthin, a lipid-soluble carotenoid, exhibits strong antioxidant activity in vitro and in animal studies, but its effectiveness in reducing exercise-induced oxidative stress in humans remains unclear due to inconsistent clinical findings. Variability in study design, supplementation protocols, and biomarker assessment contributes to these discrepancies. Advanced oxidation protein products (AOPP), chlorinated cross-linked plasma proteins generated via myeloperoxidase-derived hypochlorous acid, serve as integrative indicators of protein oxidative damage and may offer improved sensitivity. This meta-analysis, prospectively registered in PROSPERO (CRD420251119762), synthesized randomized controlled trials (RCTs) published through August 2025 across major databases. Eligible trials examined oxidative or inflammatory responses to astaxanthin supplementation (4-28 mg·day-1 for 4 days to 12 weeks). Standardized mean differences (SMDs) were pooled using random-effects models, with heterogeneity and sensitivity analyses performed. Seven RCTs involving 188 participants met inclusion criteria. Astaxanthin significantly reduced AOPP (SMD =  - 1.06; 95% CI - 1.49 to - 0.62; I2 = 48%), indicating decreased protein-level oxidative stress, consistent with proposed mechanisms such as radical scavenging, modulation of myeloperoxidase activity, and Nrf2 pathway activation. Other oxidative or injury-related biomarkers (MDA/TBARS, SOD, SH, CK, IL-6) showed no significant changes, likely reflecting assay variability, insufficient dosing, or limited statistical power. Overall, astaxanthin may attenuate protein oxidation, but broader physiological or performance benefits remain unconfirmed. Larger, longer-duration RCTs with standardized biomarker timing and dosing are needed to clarify its clinical relevance.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-026-04730-1.
    Keywords:  Astaxanthin; Exercise physiology; Oxidative stress; Sports nutrition
    DOI:  https://doi.org/10.1007/s13205-026-04730-1
  11. J Gerontol A Biol Sci Med Sci. 2026 Feb 14. pii: glag039. [Epub ahead of print]
    Striatal Dopamine and Skeletal Muscle Energy Metabolism in Older Adults.
    Caterina Rosano, Nico I Bohnen, Brian Lopresti, Lana M Chahine, Haley N Barnes, Stephanie L Studenski, Nancy W Glynn, Anne B Newman, David J Marcinek, Russell T Hepple, Paul Coen.
       BACKGROUND: Dopamine (DA) in the central nervous system is considered a master regulator of mobility performance and vigor, but its mechanistic relationship with skeletal muscle energetics is unclear.
    METHODS: We tested the cross-sectional association of striatal DA and skeletal muscle mitochondrial function in 146 older adults participating in the Study of Muscle, Mobility and Aging (75.4 years old, 54% women). Striatal DA was measured using (+)-a-[11C] dihydrotetrabenazine (DTBZ) PET imaging for the limbic, sensorimotor, and executive control subregions. Mitochondrial capacity to produce ATP (ATPmax, mM ATP/s) was measured in vivo using 31P magnetic resonance spectroscopy after repeated voluntary muscle contractions. Ex-vivo respirometry assays from biopsies of resting muscle captured complementary aspects of mitochondrial function under optimal conditions.
    RESULTS: In multivariable linear regression models, [11C]DTBZ in the limbic striatum, but not other subregions, was positively associated with greater ATPmax in vivo, independent of demographics, muscle volume, leg power, white matter hyperintensities, gray matter atrophy, moderate-to-vigorous physical activity and diabetes (β  =  0.275, standard error 0.108, p = 0.019). [11C]DTBZ was not associated with the ex-vivo mitochondrial respiration markers (p > 0.2).
    CONCLUSIONS: The role of striatal limbic DA and the energetic capacity of skeletal muscles should be further investigated in older adults.
    Keywords:  Limbic Network; Muscle Energetics; Striatal Dopamine
    DOI:  https://doi.org/10.1093/gerona/glag039
  12. J Gerontol B Psychol Sci Soc Sci. 2026 Feb 14. pii: gbag013. [Epub ahead of print]
    Sex as a Moderator of the Association between Cardiorespiratory Fitness and Depressive Symptoms in Older Adults.
    Cristina Molina-Hidalgo, Michelle A Villarroel, Lauren E Oberlin, Rae Harrison, Anna L Marsland, Carla Urdaneta, Haiqing Huang, Shivangi Jain, Lu Wan, Audrey M Collins, Melanie Mack, George Grove, Arthur F Kramer, Charles H Hillman, John M Jakicic, Eric Vidoni, Jeffrey Burns, Edward McAuley, Chaeryon Kang, Swathi Gujral, Kirk I Erickson.
       OBJECTIVES: The study investigates sex differences in how cardiorespiratory fitness (CRF) and accelerometry-based physical activity relate to depressive symptoms in community-dwelling older adults. We hypothesized that the relationship between higher CRF and PA levels with lower depressive symptoms would be more prominent in women relative to men.
    METHODS: Participants included 648 community-dwelling adults aged 65-80 (71% women (n = 461); mean age [SD] = 69.88 [3.75]) without evidence of clinical depression (Geriatric Depression Scale score <9). CRF was assessed using a graded exercise test, and PA (light PA, moderate-to-vigorous PA [MVPA]) was assessed using a 7-day actigraphy protocol. Subsyndromal depressive symptoms were evaluated using the Hospital Anxiety and Depression Scale. Multiple linear regression analyses were performed to examine the relationships between CRF, light PA, MVPA, and depressive symptoms, adjusting for age, sex, years of education, body mass index, and anxiety symptoms, and to evaluate the moderating role of sex.
    RESULTS: Higher CRF and greater amounts of MVPA and light PA were associated with fewer depressive symptoms (β=-0.12, p = 0.010; β=-0.09, p = 0.021; and β=-0.13, p < 0.001, respectively) within the overall sample. However, moderation analysis by sex revealed that higher CRF was associated with fewer depressive symptoms only among female participants (β=-0.19, p < 0.001). Sex moderation effects were not observed for light PA or MVPA.
    DISCUSSION: These findings suggest CRF is a key physiological correlate of subsyndromal depressive symptoms in late life, particularly for women. Understanding sex-specific responses to PA may inform tailored prevention and intervention strategies targeting mood symptoms prior to full clinical expression of depression.
    CLINICAL TRIAL REGISTRATION: NCT02875301.
    Keywords:  Exercise; Mental health; Mood; Physical activity; Subclinical depression
    DOI:  https://doi.org/10.1093/geronb/gbag013
  13. J Gerontol A Biol Sci Med Sci. 2026 Feb 14. pii: glag034. [Epub ahead of print]
    Benefits of Oral Nitrite Supplementation on Mitochondrial Respiration and Physical Function In Older Adults.
    Daniel E Forman, Subashan Perera, Sruti Shiva, Nancy W Glynn, Tara Teahan Stakich, Sofhia V Ramos, Giovanna Distefano, Cody Wolf, Angelina Kendi, Adam Sterczala, Ian J Sipula, Fiona M Bello, Michael J Jurczak, Frank C Sciurba, Mark T Gladwin, Anne B Newman, Paul M Coen.
       BACKGROUND: Age-associated decline in mitochondrial oxidative capacity is associated with increased risk of disease, frailty, and disability. Oral nitrite and nitrate supplementation have been demonstrated to improve mitochondrial energetics and physical function in younger adults, but effects in older adults (age ≥70 years) remain unclear.
    METHODS: Randomized, placebo controlled, double-blind, 2-arm trial with a parallel group design to examine the effect of 20 mg sodium nitrite supplements administered three times a day for 12 weeks versus placebo in older (age ≥70 years) sedentary adults. Change in muscle mitochondrial respiration (complex I and II supported maximal oxidative phosphorylation [CI&II MaxOXPHOS]) was the primary outcome. Platelet bioenergetics, cardiorespiratory fitness, and other physical function measures were also assessed.
    RESULTS: 64 adults (75.7 ± 5.7 years) completed the trial. Nitrite supplementation was not associated with improvements in skeletal muscle mitochondrial respiration, nor improvements in exercise capacity and physical function. However, platelet mitochondrial respiration changed significantly following an acute dose of oral nitrite. Notably, while nitrite levels increased 16 to 30-fold in plasma following an acute dose, levels increased only 1.6 fold in skeletal muscle.
    CONCLUSIONS: The divergent response of skeletal muscle versus platelet mitochondrial respiration in response to nitrite supplementation suggest tissue-specific pharmacokinetics and pharmacodynamics that likely impact on the efficacy of nitrite supplementation. Results also suggest there may be age-related changes in drug delivery, metabolism, and mitochondrial responsiveness compared to nitrite/nitrate previously demonstrated in younger adults.
    Keywords:  Gerotherapeutics; Mitochondrial respiration; Nitric oxide signaling; Pharmocodynamics; Physical function; aging; exercise capacity; geroscience; mitochondrial respiration; nitrite
    DOI:  https://doi.org/10.1093/gerona/glag034
  14. J Agric Food Chem. 2026 Feb 17.
    Eicosapentaenoic Acid Attenuates Type 2 Diabetes Mellitus-Related Sarcopenia in Mice and Its Potential Mechanisms.
    Shi-Xiang Wu, Meng-Qing Zhou, Han-Ni Wei, Yan Zheng, Zi-Jian Wu, Xin-Yue Zhao, Qing-Yan Zou, Cheng-Yu Yang, Ao Tian, Yu-Hong Yang, Chang-Sheng Zhao, Lei Du.
      This study investigated the therapeutic potential of eicosapentaenoic acid (EPA) against type 2 diabetes mellitus (T2DM)-related sarcopenia. In a streptozotocin/high-fat diet-induced T2DM mouse model, 24 week EPA supplementation improved insulin resistance, reduced advanced glycation end product (AGE) accumulation, and preserved skeletal muscle mass and strength. In vitro, the EPA mitigated high-glucose/AGE-induced atrophy in C2C12 myotubes. Mechanistically, EPA counteracted T2DM-related sarcopenia through improving insulin resistance and glycemic control, lowering AGE accumulation, and attenuating inflammatory response and oxidative damage in skeletal muscle. Moreover, EPA protected mitochondrial integrity in skeletal muscle cells by activating the AMPK/Sirt1/PGC-1α axis to boost mitochondrial biogenesis and alleviated excessive apoptosis via inhibiting the intrinsic apoptotic pathway. Furthermore, the EPA maintained protein metabolic homeostasis in skeletal muscle via restoring the PI3K/Akt/mTOR signaling cascade and suppressing the FoxO3a- and NF-κB-mediated ubiquitin-proteasome pathway. Overall, our findings suggest EPA as a promising nutritional intervention against T2DM-related sarcopenia.
    Keywords:  EPA; T2DM; mitochondrial quality; protein metabolic homeostasis; sarcopenia
    DOI:  https://doi.org/10.1021/acs.jafc.5c11649
  15. Maturitas. 2026 Feb 10. pii: S0378-5122(26)00052-6. [Epub ahead of print]207 108875
    Time since menopause and a circulating metabolomic signature for sarcopenia risk: Data from 68,064 women from the UK Biobank.
    Xiaoyu Zhang, Bo Xie, Chunying Fu, Qi Wang, Juan Li, Dongshan Zhu.
       BACKGROUND: Menopause-related metabolic alterations may increase susceptibility to sarcopenia, yet the longitudinal dimension of reproductive ageing-namely time since menopause-has not been investigated using an innovative metabolomic strategy that captures dynamic, multi-pathway metabolic changes and constructs a validated metabolomic signature related to time since menopause. We aimed (1) to identify a plasma metabolomic profile related to time since menopause, (2) to evaluate the independent associations of time since menopause and the metabolomic signature with sarcopenia and its components, and (3) to quantify the mediation effect exerted by this profile.
    METHODS: We analyzed 68,064 naturally postmenopausal women (4406 with sarcopenia) from the UK Biobank and validated findings in 5971 women with repeat assessments. Time since menopause was defined as baseline age minus age at natural menopause. Nuclear magnetic resonance spectroscopy was used to quantify 251 plasma metabolites. Elastic net regression was applied to derive a metabolomic signature related to time since menopause, which was validated by correlation analysis. Multivariable logistic regression estimated odds ratios (ORs) for sarcopenia, low strength, mass, and performance; mediation was assessed via bootstrapping.
    RESULTS: Eighty-six metabolites spanning lipid, amino acid, and glycolytic pathways-closely linked to energy metabolism and protein homeostasis relevant to muscle physiology-comprised the signature related to time since menopause (baseline r = 0.27, P < 0.001). Each 5-year increase in time since menopause was associated with higher odds of sarcopenia (OR 1.13, 95% CI 1.09-1.16), and each 1-SD higher signature score was independently associated with sarcopenia (1.06, 1.02-1.10). The metabolomic signature mediated 13.3% of the association between time since menopause and sarcopenia.
    CONCLUSIONS: A distinctive, multi-pathway metabolomic signature tracks time since menopause and partly mediates its association with sarcopenia. Reflecting coordinated dysregulation in lipid and amino acid metabolism, this signature may provide a molecular link between reproductive ageing and postmenopausal muscle decline and has potential utility as a non-invasive biomarker for early risk stratification.
    Keywords:  Menopause; Metabolomics; Postmenopausal women; Sarcopenia; Time since menopause
    DOI:  https://doi.org/10.1016/j.maturitas.2026.108875
  16. Front Aging. 2026 ;7 1743142
    Molecular pathways linking chronic psychological stress to accelerated aging: mechanisms and interventions.
    Othman A Alhazzaa, Hanin M Abahussin, Majed A Majrashi, Maryam S Alotaibi, Mohammad N Alkhrayef, Ziyad A Alhamdan, Abdullah O Alawad.
      Chronic psychological stress refers to repeated or prolonged exposure to adverse social or emotional threats that exceed an individual's adaptive capacity. It is recognized as a risk factor for aging-associated diseases. A growing body of research has shown that there is a link between chronic psychological stress and accelerated aging. Here, we highlight recent findings on the interconnected relationship between chronic psychological stress and major aging hallmarks, including mitochondrial dysfunction, telomere attrition, cellular senescence, epigenetic alterations, inflammation, and genomic instability. We discuss the mechanisms by which chronic psychological stress may drive this effect and explore intervention strategies that could mitigate its adverse effects and promote healthy aging. Moreover, we address current research gaps and propose future research directions to improve our understanding of the intricate relationship between psychological stress and aging.
    Keywords:  aging; epigenetic; inflammation; mitochondria; psychological stress; stress response; telomere
    DOI:  https://doi.org/10.3389/fragi.2026.1743142
  17. Medicines (Basel). 2026 Jan 22. pii: 2. [Epub ahead of print]13(1):
    Antioxidant Delivery Revisited: The Promise of Nanostructured Lipid Carriers.
    Leif Behar, Holly Siddique.
      Natural products have an invaluable therapeutic effect on human health. Natural antioxidants, including beta-carotene, turmeric, and polyphenols, are recognised for their health benefits but face significant barriers related to insufficient solubility, instability, volatility, and diminished bioavailability, which limit their therapeutic efficacy in drug delivery systems. Therefore, encapsulation of natural products in a carrier addresses the above concern. Drug delivery systems, such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), are promising carriers for effective release, consisting of solid and liquid lipids, which enhance efficiency, stability, and controlled release, thereby minimising bioavailability limitations. This review consolidates current studies on the formulation methodologies, mechanisms of action, and therapeutic applications of NLCs, emphasizing their use in the treatment of conditions such as cancer, neurological disorders, and cardiovascular diseases. The results demonstrate that NLCs substantially enhance the bioavailability and therapeutic efficacy of antioxidants, thereby improving their targeted administration and clinical effects. Nonetheless, difficulties in clinical translation remain, including drug loading capacity, regulatory authorisation, and the need for pervasive research on cytotoxicity. This article highlights important areas for future inquiry, specifically the optimisation of NLC formulations, the enhancement of targeting accuracy, and the resolution of safety issues to enhance their clinical application.
    Keywords:  antioxidant delivery; bioavailability enhancement; cancer treatment; controlled release; drug delivery systems; nanostructured lipid carriers (NLCs); natural compounds; neurodegenerative diseases; polyphenols; therapeutic applications
    DOI:  https://doi.org/10.3390/medicines13010002
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