bims-mistre 2026-02-08 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2026–02–08
twenty-two papers selected by
Ellen Siobhan Mitchell, MitoQ

Leveraging mitochondrial stress to improve healthy aging.
Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis.
Ketone Monoester Increases Skeletal Muscle Power and Energy Turnover in Older but Not Young Men Without Affecting Metabolic Economy: A Controlled, Double Blind, Cross-Over Trial.
Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.
Enhancing Mitophagy with PEP-1-CAT Attenuates Vascular Inflammation and Atherogenesis in Mice.
Supplementation with Lycium barbarum glycopeptide (LbGP) rescues the quality of aged oocytes.
Targeting mitochondrial quality control in diabetic kidney disease: emerging therapeutic opportunities.
Stimulatory Effects of (+)-Epicatechin on Mitochondrial Biogenesis and Function in Skeletal Muscle of Aged Rats: Underlying Mechanisms.
Association of Physical Frailty With Serum Growth Differentiation Factor-15 and Cognitive Decline: A Cross-Sectional Study.
Elevating Circulating L-Kynurenine Promotes Frailty in Aging Mice.
Precision health targeting TMAO in postmenopausal women: polyphenol effects modulated by urolithin A and equol metabotypes in a randomised, placebo-controlled crossover trial.
Effects of Ashwagandha (Withania somnifera) on Mental Health in Adults: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials.
Crocin alleviates doxorubicin-mediated cardiotoxicity by activating PINK1-dependent cardiomyocyte mitophagy.
Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.
Association of mitochondrial oxidative capacity with physical fitness in ageing: the Baltimore longitudinal study of ageing.
Remission of impaired glucose tolerance by anthocyanin supplementation: a randomized, double-blind, placebo-controlled trial.
Bridging Psychological Stress and Skin Cellular Aging: Flavonoids as a Dual-Action Therapeutic Strategy.
Andrographolide analogues are agonists of the estrogen receptor alpha in vitro and in vivo.
Blood circulating cell-free mitochondrial DNA as a potential biomarker for major depressive disorder: a meta-analysis.
Overnight wakefulness impairs next-day postprandial glucose in young women independent of sex hormones.
Urolithin A alleviates vascular remodeling through mitochondrial SIRT3-mediated SOD2 deacetylation and antioxidation in hypertensive rats.
Cognitive function in relation to age at menopause: Insights from the English longitudinal study of aging.

Sports Med Health Sci. 2026 Jan;8(1): 23-33

Leveraging mitochondrial stress to improve healthy aging.

Abril Gorgori-Gonzalez, Silvana Soto-Rodriguez, Eva Tamayo-Torres, Esther Garcia-Dominguez, Vicente Sebastia, Juan Gambini, Gloria Olaso-Gonzalez, Maria Carmen Gomez-Cabrera.

  Aging is characterized by a progressive decline in physiological function, driven by intrinsic mechanisms (primary aging) and modifiable factors (secondary aging), ultimately leading to multimorbidity, disability, and mortality. Mitochondrial dysfunction, a major hallmark of aging, plays a central role in the loss of muscle mass and strength observed in frailty and sarcopenia. With age, mitochondrial quality control processes, including biogenesis, mitophagy, and dynamics, become dysregulated, impairing energy metabolism and muscle homeostasis. Mitochondrial dysfunction correlates with clinical biomarkers of sarcopenia and frailty, such as the decrease in walking speed and muscle strength, making it a therapeutic target for mitohormesis-based strategies aimed at preserving functional capacity. Mitohormetic agents induce reversible mitochondrial stress, triggering adaptive responses that enhance function. Among these interventions, physical exercise, particularly endurance and resistance training (RT), has been reported to be among the most effective, as it may modulate mitochondrial biogenesis, dynamics, and mitophagy through increases in proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and mitochondrial transcription factor A (TFAM) expression, mitochondrial deoxyribonucleic acid (mtDNA) copy number, and mitochondrial content. Chronic RT can also elevate fusion and fission markers, potentially as a compensatory mechanism to mitigate mitochondrial damage. Apart from exercise, mitohormetic compounds such as harmol and piceid are emerging as promising supplements in the aging field. By modulating mitochondrial bioenergetics and dynamics, they may complement lifestyle-based interventions to improve mitochondrial fitness and extend health span.

Keywords:  Frailty; Mitochondrial dysfunction; Mitohormesis; Muscle homeostasis; Phytochemicals; Resistance training

DOI:  https://doi.org/10.1016/j.smhs.2025.10.003
Neurobiol Aging. 2026 Jan 27. pii: S0197-4580(26)00012-6. [Epub ahead of print]161 47-63

Human in vitro and rodent in vivo models highlight progressive mitochondrial dysfunction as a starting point of cerebral amyloidosis.

Zahra Motamed, Gisela Novack, Daniel Heutschi, Carine Gaiser, Corina Garcia, Sonia Do Carmo, A Claudio Cuello, Laura Morelli, Laura Suter-Dick.

  Mitochondrial dysfunction is a well-established hallmark of Alzheimer's disease (AD), particularly in the context of amyloid-beta (Aβ) accumulation. Here, we explored the progression of mitochondrial impairment associated with cerebral amyloidosis in human and rodent systems expressing AD-relevant APP mutations. We investigated mitochondrial function, dynamics, and degradation in human neural progenitor cells differentiated for two and six weeks, carrying the APP (Swedish/London) mutations. These analyses were complemented by studies in 3- and 9-month-old McGill-R-Thy1-APP transgenic (Tg) rats expressing the APP (Swedish/Indiana) mutations. We observed a consistent accumulation of pathogenic Aβ species associated with mitochondrial damage. In vitro, early indicators of oxidative stress and initial alterations in mitochondrial network dynamics were evident, including increased mitochondrial reactive oxygen species and elevated total DRP1 levels. Later, after 6 weeks of differentiation, significant mitochondrial dysfunction emerged, including reduced membrane potential, increased mitochondrial network fragmentation, and decreased GSH/GSSG ratio. Mitophagy was also disrupted, as evidenced by reduced localization of TOMM20 to the lysosomes, suggesting impaired mitochondrial clearance. Similarly, hippocampal mitochondria fraction of 9-month-old Tg rats showed elevated fission markers, nitrosative stress, and mitochondrial p62 accumulation, which were absent in 3-month-old Tg animals. Hence, we identified both early and late molecular alterations in mitochondrial homeostasis revealing accumulation of mitochondrial stress, altered dynamics, and mitophagy failure in response to sustained Aβ release. Our results underscore mitochondrial vulnerability during early amyloidosis, identifying it as a potential therapeutic target at initial disease stages. It also reinforces the utility of in vitro models for studying cerebral amyloid pathologies.

Keywords:  APP mutations; Alzheimer´s disease; Amyloid beta; Amyloidosis; Mitochondrial impairment; Mitophagy

DOI:  https://doi.org/10.1016/j.neurobiolaging.2026.01.006
Acta Physiol (Oxf). 2026 Mar;242(3): e70161

Ketone Monoester Increases Skeletal Muscle Power and Energy Turnover in Older but Not Young Men Without Affecting Metabolic Economy: A Controlled, Double Blind, Cross-Over Trial.

Ole Emil Andersen, Ryan Godsk Larsen, Niels Møller, Anders Stouge, Steffen Ringgaard, Kristian Overgaard, Niels Jessen.

   AIM: Ketosis may represent a therapeutic target for age-related impairments in skeletal muscle function. This study investigated acute effects of ketosis on metabolic economy, mitochondrial function, and contractile parameters in skeletal muscle of young and older adults.
METHODS: Twelve young (20-25 years) and twelve older (65-85 years) healthy men, matched by age-adjusted V̇O2max, participated in a randomized, crossover, double-blind intervention with ingestion of ketone monoester or placebo on separate study days. On both days, a low-dose, continuous glucose infusion blocked endogenous ketone production. Metabolic economy, oxidative capacity, muscle performance, intramuscular pH, and relative decline in peak power were assessed in the tibialis anterior through phosphorous MR spectroscopy (31P-MRS) and dynamometer recordings. Mitochondrial function of the quadriceps femoris muscle was assessed by high-resolution respirometry.
RESULTS: Ketosis had no effect on metabolic economy in either young or older participants. The older group showed lower metabolic economy compared to the young group. In older participants, ketones increased ATP production and time-torque derived work capacity. Oxidative capacity was similar between groups and remained unaffected by ketones. In the older group, ketones improved peak power and increased both muscle relative decline in peak power and contraction-induced pH decline. Complex I + II respiration was lower in older compared to young participants, with no effect of ketones.
CONCLUSION: Ketosis enhanced skeletal muscle work capacity and ATP production in older but not young adults, suggesting an age-specific effect of ketone bodies on muscle function that operates independently of changes in metabolic economy and mitochondrial function. These findings support ketosis as a promising ergogenic therapy for older adults.
TRIAL REGISTRATION: The study was pre-registered at clinicaltrials.gov (NCT05732909).

Keywords:  aging; bioenergetics; contractile performance; ketone bodies; metabolic economy; mitochondrial function; skeletal muscle

DOI:  https://doi.org/10.1111/apha.70161
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699119. [Epub ahead of print]

Vitamin B12 Improves Skeletal Muscle Mitochondrial Biology in Aged Mice.

Abigail R Williamson, Angad Yadav, Wenxia Ma, Susan Schmitt, Shelby Rorrer, Lauren E Odom, Luisa F Castillo, Chloe T Purello, Olga V Malysheva, James Mobley, Martha Field, Anna E Thalacker-Mercer.

Age-related skeletal muscle deterioration is a commonly reported disability among older adults, attributed to several factors including mitochondrial dysfunction, a major hallmark of aging. Therapies to attenuate or reverse mitochondrial decline are limited. Despite identified positive relationships between vitamin B12 (B12) and mitochondrial biology, the impact of B12 supplementation on skeletal muscle mitochondria, in advanced aged, has not been examined. Thus, the impact of B12 supplementation on skeletal muscle mitochondrial biology was examined in (i) aged female mice, given 12 weeks of B12 supplementation (SUPP) or vehicle control, and (ii) in human primary myotubes. In the mouse model, mitochondrial DNA and content were measured with PCR and citrate synthase activity, respectively; mitochondrial morphology was examined using transmission electron microscopy; mitochondrial function was examined using extracellular metabolic flux analysis; and proteins and pathway enrichment was identified with proteomics. In the cell model, ROS and glutathione was measured using luminescent assays. The results demonstrated that SUPP in aged mice increased muscle mitochondrial content and improved morphology. Further, differentially expressed proteins were enriched in TCA cycle, OXPHOS, and oxidative stress pathways. In the cell model, B12 supplementation reduced ROS levels. This is the first study, to our knowledge, examining the impact of B12 supplementation on skeletal muscle mitochondrial biology in aged female mice. Results suggest that B12 supplementation improves mitochondrial biology in aged female mice.

DOI: https://doi.org/10.64898/2026.01.13.699119
Inflammation. 2026 Feb 05.

Enhancing Mitophagy with PEP-1-CAT Attenuates Vascular Inflammation and Atherogenesis in Mice.

Shuang Wei, Lei Zhang, Xuan-Ren Wang, Fei Zheng, Yu-Wen Yan, Lu Wang, Jian-Ye Yang, Jian Fu, Zhi-Jian Wang.

  The gradual decline of endothelial function and the intensification of inflammatory responses form the basis for the occurrence and development of age-related diseases such as atherosclerosis (AS). Mitochondrial dysfunction-manifested by excessive reactive oxygen species (ROS) production, reduced mitochondrial membrane potential, and impaired mitophagic flux-and sterile inflammation are hallmarks of aged vasculature. We investigated whether bolstering mitochondrial quality control via the novel cell-penetrating antioxidant PEP-1-Catalase (CAT) could mitigate these key features of vascular aging. To model age-associated vascular pathology, ApoE⁻/⁻ mice were fed a high-fat diet (HFD) and treated with PEP-1-CAT. Endothelial cell function, plaque burden, and inflammation were analyzed. In vitro, human endothelial cells (HUVECs) were subjected to inflammatory stress and treated with PEP-1-CAT, with or without modulators of mitophagy. We assessed mitochondrial ROS, membrane potential, NOD-like receptor protein 3 (NLRP3) inflammasome activation, and the PINK1-Parkin pathway. PEP-1-CAT treatment significantly ameliorated atherogenesis and improved features of plaque stability in mice. It suppressed vascular oxidative stress, restored mitochondrial membrane potential, enhanced mitophagic flux, and inhibited NLRP3-driven inflammation. In endothelial cells, PEP-1-CAT attenuated mitochondrial oxidative stress and dysfunction. Crucially, it activated the PINK1-Parkin pathway to promote mitophagy, which was essential for its anti-inflammatory effects, as mitophagy inhibition abrogated the suppression of the NLRP3 inflammasome. Our findings demonstrate that targeting mitochondrial health with PEP-1-CAT alleviates hallmarks of atherosclerotic vascular pathology, including endothelial dysfunction and inflammation, by enhancing mitophagy. This strategy of restoring mitochondrial quality control presents a promising therapeutic approach to delay atherosclerotic vascular pathology.

Keywords:  Atherosclerosis; Mitochondrial damage; Mitophagy; NF-κB; NLRP3 inflammasome; PEP-1-CAT

DOI:  https://doi.org/10.1007/s10753-026-02463-0
J Ethnopharmacol. 2026 Feb 04. pii: S0378-8741(26)00169-8. [Epub ahead of print] 121318

Supplementation with Lycium barbarum glycopeptide (LbGP) rescues the quality of aged oocytes.

Aolei Guo, Ruixin Shi, Sipei Liu, Yang Zhang, Yan Mao, Guijun Yan, Guangyi Cao.

   ETHNOPHARMACOLOGICAL RELEVANCE: Lycium barbarum L. (goji berry), a traditional medicinal and edible herb, has long been employed for its anti-aging, vision-enhancing, and anti-inflammatory properties. Lycium barbarum glycopeptide (LbGP), a major bioactive glycoconjugate isolated from this plant, possesses documented antioxidant and immunomodulatory activities. However, its specific therapeutic efficacy in counteracting reproductive aging and the precise mechanisms underlying its protective effects on oocyte quality remain to be fully elucidated.
AIM OF THE STUDY: To investigate the restorative effects of LbGP on ovarian function and oocyte quality in aged mice and to decipher the underlying mechanisms involving both oocyte-intrinsic metabolic regulation and extrinsic ovarian microenvironment remodeling.
MATERIALS AND METHODS: A reproductive aging model was established using naturally aged female mice supplemented with LbGP. Follicular development and oocyte quality were assessed via histological analysis, in vitro fertilization (IVF), and early embryonic culture. Mitochondrial function and oxidative stress levels were monitored using live-cell imaging. Mechanistic insights were generated through integrated proteomic analysis of oocytes and single-cell RNA sequencing (scRNA-seq) of ovarian tissues to identify key metabolic pathways and cellular composition changes.
RESULTS: LbGP supplementation significantly promoted follicular development, enhanced oocyte maturation competence, and improved subsequent early embryonic potential compared to untreated aged mice. Mechanistically, proteomic analysis revealed that LbGP restored mitochondrial function in aged oocytes by activating PPAR signaling pathways, leading to reduced intracellular reactive oxygen species (ROS) accumulation and DNA damage. Furthermore, ovarian single-cell transcriptomics demonstrated that LbGP systemically remodeled the aged ovarian microenvironment by increasing functional granulosa cell populations, reducing pro-inflammatory immune cells, and repairing intercellular communication networks.
CONCLUSIONS: LbGP delays reproductive aging by concurrently restoring mitochondrial function in aged oocytes and remodeling the ovarian microenvironment. These findings provide modern pharmacological evidence supporting LbGP as a promising natural therapeutic candidate capable of improving oocyte quality and enhancing fertility outcomes in women of advanced maternal age.

Keywords:  Lycium barbarum glycopeptide (LbGP); Mitochondrial function; Ovarian microenvironment; Oxidative stress; Reproductive aging

DOI:  https://doi.org/10.1016/j.jep.2026.121318
Ren Fail. 2026 Dec;48(1): 2620218

Targeting mitochondrial quality control in diabetic kidney disease: emerging therapeutic opportunities.

Jiajun Luo, Fuer Lu, Magdalena Cuciureanu, XiaoHu Xu, Hui Dong, Minmin Gong.

  Diabetic kidney disease (DKD) is one of the most common microvascular complications among individuals with diabetes and has become a leading cause of end-stage renal disease (ESRD). The mechanisms underlying DKD are complex, and effective therapeutic strategies remain limited. Mitochondrial dysfunction occurs earlier than proteinuria and renal morphological changes, and is considered a key event in the progression of DKD. Mitochondrial dysfunction in diabetic kidneys involves several processes, including excessive production of mitochondrial reactive oxygen species, reduced mitochondrial biogenesis, impaired mitophagy, and disturbances in mitochondrial dynamics. Recently, mitochondria-targeted drugs, including antioxidants, CD38 inhibitors, glucose-linked transport 2 sodium inhibitor (SGLT2i), and compounds derived from traditional Chinese medicine, have shown positive effects in animal experiments or clinical trials. This review aims to highlight the role of mitochondrial quality control and dysfunction in DKD, the specific mitochondrial regulators of different renal cell types, as well as the therapeutic potential of some emerging drugs and the limitations of existing preclinical evidence, thereby identifying promising therapeutic targets and strategies for the disease.

Keywords:  Diabetic kidney disease; mitochondrial dysfunction; mitochondrial quality control; oxidative stress

DOI:  https://doi.org/10.1080/0886022X.2026.2620218
J Med Food. 2026 Feb 04. 1096620X261421080

Stimulatory Effects of (+)-Epicatechin on Mitochondrial Biogenesis and Function in Skeletal Muscle of Aged Rats: Underlying Mechanisms.

Israel Ramirez-Sanchez, Rosa Ordoñez-Razo, Veronica Najera, Guillermo Ceballos, Francisco Villarreal.

  Mitochondrial dysfunction affects skeletal muscle (SkM) function and is critical in the etiology of age-related sarcopenia. The sirtuin 1-PGC1α pathway is a key regulator of mitochondrial mass, structure, and function. However, pathway activity decreases with aging. Cacao flavanols show promise in their ability to activate mitochondrial pathways. We evaluated the capacity of the flavanol (+)-epicatechin (+Epi) to stimulate such a pathway and favorably impact mitochondrial and oxidative stress (OS)-associated endpoints in aged SkM. Using 23-month-old male Sprague-Dawley rats, an 8-week oral administration of +Epi (1 mg/kg/day) was implemented, and results were compared versus vehicle-treated controls. Assessments included the nicotinamide adenine dinucleotide (NAD)/sirtuin 1/PGC1α pathway, acetylated proteins levels, mitochondrial function and biogenesis, as well as OS-related endpoints in SkM. +Epi increased the NAD/NADH ratio, activation of sirtuin 1, the deacetylation of nuclear protein content, including that of PGC1α. Also, +Epi induced increases of TFAM and NRF1 mRNA levels, deacetylation of mitochondrial complex I and V, increases in complex I activity, sirtuin 3, complexes I and V, mitofilin, and TFAM protein levels. SkM citrate synthase activity and ATP content increased with +Epi. OS markers in proteins and lipids were reduced, while buffering systems (superoxide dismutase 2 and catalase protein and activities) increased. In white blood cells, we documented serial reductions in mitochondrial DNA content and citrate synthase activity with aging, which were either fully or partially reversed with +Epi. Results demonstrate that +Epi treatment yields positive effects on mitochondrial biogenesis and function, leading to decreased OS and improved SkM bioenergetics in aged rats.

Keywords:  atrophy; epicatechin; mitochondria

DOI:  https://doi.org/10.1177/1096620X261421080
Geriatr Gerontol Int. 2026 Feb;26(2): e70377

Association of Physical Frailty With Serum Growth Differentiation Factor-15 and Cognitive Decline: A Cross-Sectional Study.

Kazuhiro Yoshiura, Yosuke Osuka, Kaori Kinoshita, Noriko Hori, Jiaqi Li, Georg von Fingerhut, Tohru Hosoyama, Daichi Shigemizu, Marie Takemura, Yasumoto Matsui, Shosuke Satake.

   AIM: Growth differentiation factor-15 (GDF-15) is a biomarker reflecting aging and cellular stress, associated with physical frailty and cognitive decline. We cross-sectionally examined whether physical frailty is involved in the association between GDF-15 and cognitive decline. Understanding this association may help to consider frailty-related cognitive decline and potential preventive approaches.
METHODS: This cross-sectional study included 134 participants aged 65 years or older, excluding those with severe renal dysfunction, immune-related diseases, and those with dementia or suspected dementia (Mini-Mental State Examination [MMSE] score ≤ 23). Serum GDF-15 levels were measured, and cognitive decline was assessed using the MMSE with a cutoff score of 27 or lower. Physical frailty was evaluated using the revised Japanese Cardiovascular Health Study criteria comprising five components: shrinking, exhaustion, weakness, slowness, and low activity.
RESULTS: A mediation analysis adjusted for age, sex, and education showed a significant indirect effect of GDF-15 on cognitive decline through physical frailty (β = 0.921, 95% confidence interval [CI]: 0.279-1.560). The total effect was also significant (β = 1.020, 95% CI: 0.030-2.010), whereas the direct effect was not significant (β = 0.100, 95% CI: -0.991 to 1.190).
CONCLUSIONS: This study suggests a potential involvement of physical frailty in the relationship between serum GDF-15 levels and cognitive decline. Serum GDF-15 levels may have potential as a clinical indicator for frailty-related cognitive decline in the future. Further longitudinal studies are needed to explore this relationship and clarify the role of GDF-15.

Keywords:  cognitive decline; cross‐sectional study; growth differentiation factor‐15; mediation analysis; physical frailty

DOI:  https://doi.org/10.1111/ggi.70377
J Cachexia Sarcopenia Muscle. 2026 Feb;17(1): e70214

Elevating Circulating L-Kynurenine Promotes Frailty in Aging Mice.

Mia Y Kawaida, Abigail L Tice, Samuel Alvarez, Jacob A Lackey, Benjamin Izaguirre, Qingping Yang, Lan Wei-LaPierre, Russell T Hepple, Terence E Ryan.

   BACKGROUND: L-Kynurenine (L-Kyn), a product of tryptophan catabolism, increases with age and has been associated with reduced physical function and increased frailty in humans. Robustly expressed in skeletal muscle, kynurenine aminotransferases (KATs) degrade L-Kyn into kynurenic acid and are regulated by the transcriptional co-regulator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α).
METHODS: The study investigated (1) if elevating L-Kyn levels via a diet intervention exacerbates an age-related decline in physical, muscle and mitochondrial functions and (2) if transgenic expression of PGC1α in skeletal muscle (MCK-PGC1α) protects against age-dependent L-Kyn associated pathology in a cohort of aging MCK-PGC1α transgenic mice and their wildtype littermates of both sexes (n = 262). Physical function was assessed longitudinally from 16 to 24 months of age using treadmill endurance capacity, grip strength, walking speed and daily physical activity. Muscle function was assessed in situ using nerve-mediated contraction of the soleus muscle. Mitochondrial energetics were assessed using high resolution respirometry and fluorescence spectroscopy.
RESULTS: MCK-PGC1α transgenic mice had significantly higher KAT expression ~2-5-fold compared with wildtype littermates (p < 0.0001 for all isoforms). A main effect of L-Kyn diet was observed for decreasing treadmill endurance capacity and daily physical activity in male mice (p ≦ 0.002). A main effect of L-Kyn diet for decreasing maximal walking speed only was found in female mice (p = 0.037). Correspondingly, L-Kyn increased frailty prevalence in male (+17%) and female (+26%) wildtype mice (p = 0.025 and 0.0001 respectively), which was mitigated by MCK-PGC1α in both sexes. Soleus muscle strength and power were not impacted by diet or genotype in either sex (p > 0.5). Mitochondrial oxidative phosphorylation function in male and female MCK-PGC1α mice was greater than wild type mice regardless of diet (p < 0.04), which is likely driven by upregulated expression of mitochondrial biogenesis related genes.
CONCLUSIONS: We conclude that PGC1α overexpression in skeletal muscle mitigates the exacerbation of physical frailty induced by elevated circulating L-Kyn in aging mice, in part through increased skeletal muscle capacity for L-Kyn metabolism due to PGC1α-induced increase in muscle KAT expression.

Keywords:  aging; frailty; mitochondria; muscle; physical function

DOI:  https://doi.org/10.1002/jcsm.70214
Food Funct. 2026 Feb 05.

Precision health targeting TMAO in postmenopausal women: polyphenol effects modulated by urolithin A and equol metabotypes in a randomised, placebo-controlled crossover trial.

María Paula Jarrín-Orozco, María García-Nicolás, María Romo-Vaquero, Concepción Carrascosa, José Berná, Julio Puigcerver, Adrián Saura-Sanmartín, María Ángeles Ávila-Gálvez, Juan Carlos Espín.

Menopause increases cardiometabolic risk, partly by reducing the protective effects of estrogens and inducing gut microbiota dysbiosis, which can promote the production of atherogenic metabolites such as trimethylamine N-oxide (TMAO). Polyphenols may reduce TMAO levels, though interindividual variability limits reproducibility. We compared urinary and serum TMAO levels, and urinary trimethylamine (TMA) and dimethylamine (DMA) levels between healthy women of reproductive age (Pre-M, n = 120) and non-medicated postmenopausal women (Post-M, n = 90) using UPLC-QqQ-MS/MS. In Post-M women, we conducted a randomised, placebo-controlled crossover study to evaluate the effects of a polyphenol-rich extract mixture containing pomegranate, Polygonum cuspidatum, and red clover (sources of ellagitannins, resveratrol, and isoflavones) on TMAO, TMA, and DMA in the whole group and after metabotyping. Because medication is common in Post-M women due to age and cardiometabolic risk, trials in non-medicated participants are challenging, yet avoiding drug-diet interactions allows clearer attribution of dietary effects. Urinary TMAO and DMA levels were higher in Post-M than in Pre-M. No changes were observed in serum TMAO. However, the intervention reduced urinary TMAO and DMA versus baseline and placebo. The effects varied by metabotype. TMAO reduction was significant in urolithin A metabotype (UMA), equol producers (EP), and lunularin non-producers (LNP). Reductions and effect sizes were most pronounced in the metabotype clusters MC3 (UMA + EP + LP) and MC7 (UMA + EP + LNP), which represented 39% of participants. DMA decreased selectively in UMA. No correlations were found between TMAO or DMA changes and BMI, age at menopause onset, or years since menopause. These findings show that polyphenol supplementation reduces urinary TMAO in a metabotype-dependent manner and support metabotyping as a precision-health strategy to mitigate cardiometabolic risk after menopause.

DOI: https://doi.org/10.1039/d5fo05461c
Complement Ther Med. 2026 Feb 03. pii: S0965-2299(26)00008-7. [Epub ahead of print] 103325

Effects of Ashwagandha (Withania somnifera) on Mental Health in Adults: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials.

Saleh A Alsanie, Fahad Saad Alhodieb, Moein Askarpour.

   BACKGROUND: Ashwagandha (Withania somnifera), as an important herbal medicine, has been increasingly recognized for its role in mental health management, particularly in reducing stress and anxiety, and reflects the growing relevance of complementary and alternative medicine in addressing psychological well-being. The present study aims to investigate its effectiveness by pooling the evidence from existing randomized controlled trials (RCTs).
METHODS: Major medical databases of PubMed, Scopus, and Web of Science Core Collection were searched. Eligible studies were included. Meta-analysis, meta-regression, non-linear dose-response analysis, and subgroup analyses were conducted. Standardized mean differences (SMDs) were calculated. P-values < 0.05 were considered as statistically significant. The study protocol was registered in the PROSPERO database (CRD420251073134).
RESULTS: Twenty-two studies met the eligibility criteria and were included. Meta-analysis revealed that supplementation with ashwagandha significantly improves stress (SMD = -5.88; 95% CI: -8.15 to -3.60), depression (SMD = -5.68; 95% CI: -8.43 to -2.94), and anxiety (SMD = -6.87; 95% CI: -8.77 to -4.97). There was significant linear (coefficient = 0.005, P = 0.031) and non-linear (P-nonlinearity = 0.005) association between dosages of administered ashwagandha and stress levels.
CONCLUSION: Current evidence suggests that ashwagandha supplementation holds promising potential in alleviating symptoms of stress, anxiety, and depression. However, to strengthen these findings and translate them into clinical recommendations, well-designed, high-quality trials are still needed to address existing heterogeneity and to establish the most effective dosages and intervention durations.

Keywords:  Anxiety Disorders; Ashwagandha; Depressive Disorder; Stress

DOI:  https://doi.org/10.1016/j.ctim.2026.103325
Free Radic Biol Med. 2026 Jan 31. pii: S0891-5849(26)00060-2. [Epub ahead of print]246 668-681

Crocin alleviates doxorubicin-mediated cardiotoxicity by activating PINK1-dependent cardiomyocyte mitophagy.

Xin Su, Teng Fan, Zeyu Liu, Yuanyuan Huang, Jun Kan, Chuwen Liang, Yuwen Chen, Zhangqi Cao, Shuangli Zhu, Sijia Li, Kai Fu, Can Pan, Fang Wang, Bei Zhang, Liwu Fu.

   INTRODUCTION: Doxorubicin (DOX) is a widely used chemotherapeutic agent, but its clinical application is limited by dose-dependent cardiotoxicity. Currently, there are no effective strategies to prevent or reverse DOX-mediated myocardial injury, highlighting the urgent need for novel therapeutic approaches.
OBJECTIVES: In this study, the cardioprotective effects of crocin, a natural compound derived from Crocus sativus, were investigated in the context of DOX-mediated cardiotoxicity.
METHODS: Cardiac function, mitochondrial morphology, ROS production, and ATP content were evaluated in both in vitro and in vivo models of DOX-mediated cardiotoxicity. RNA sequencing was performed to identify key regulatory pathways affected by crocin. Mitophagy-related mechanisms were investigated through molecular and cellular assays, including immunofluorescence and Western blot analysis of PTEN-induced kinase 1 (PINK1)-associated signaling. PINK1 knockdown and mitophagy inhibition were performed to assess the impact on the cardioprotective effects of crocin.
RESULTS: Crocin treatment preserved cardiac function and mitigated DOX-mediated myocardial injury in both in vitro and in vivo models, as evidenced by restored left ventricular ejection fraction, reduced mitochondrial ROS accumulation, restoration of ATP production, and improved mitochondrial morphology. Transcriptomic analysis revealed that crocin upregulated PINK1 expression, a key initiator of mitophagy. Functional assays further confirmed that crocin restored mitophagy activity suppressed by DOX exposure. The cardioprotective effects of crocin were abolished upon PINK1 knockdown or mitophagy inhibitor, highlighting the essential role of PINK1-dependent mitophagy in mediating crocin's effects.
CONCLUSIONS: Crocin protects against doxorubicin-induced cardiotoxicity by activating PINK1-mediated mitophagy and maintaining mitochondrial homeostasis. These findings highlight crocin as a potential therapeutic agent for mitigating DOX-mediated cardiotoxicity.

Keywords:  Cardiotoxicity; Crocin; Doxorubicin; Mitophagy; PTEN-induced kinase 1

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.040
Curr Opin Neurol. 2026 Jan 30.

Peripheral alterations of mitochondrial function and mitophagy in Alzheimer's disease: from fundamental research to clinical perspectives.

Fanny Eysert, Gaëlle Deportes, Elodie Delaquaize, Mounia Chami.

   PURPOSE OF REVIEW: Alzheimer's disease (AD) is commonly defined by its hallmark brain pathologies, yet mounting evidence shows that metabolic impairment particularly linked to mitochondrial dysfunction, is a central and systemic feature of the disease. This review highlights consistent abnormalities in mitochondrial function, and turnover (mitophagy) across multiple AD-derived peripheral cells, including skin fibroblasts, lymphocytes, platelets, and peripheral blood mononuclear cells. We also report on potential peripheral AD biomarkers linked to mitochondria dysfunction in AD.
RECENT FINDINGS: Mitochondrial abnormalities in peripheral cells from individuals with AD robustly correlate with disease development. These mitochondrial dysfunctions mostly include reduced respiratory chain activity, increased accumulation of reactive oxygen species (ROS), altered mitochondrial membrane potential, and consequently decreased ATP production. Studies have also identified a complex pattern of mitochondrial hyperactivity and hypoactivity in peripheral cells of AD patients that appears to depend on the stage of AD and whether the disease is sporadic or familial. Furthermore, multiple steps of the mitophagy pathway are disrupted in peripheral cells as AD progresses. Finally, biochemical and proteomic analyses of peripheral fluids further support the loss of mitochondrial homeostasis in AD patients.
SUMMARY: Collectively, the reviewed findings support mitochondrial homeostasis disruption as a core pathophysiological component of AD and a promising target for biomarker development and therapeutic intervention.

Keywords:  Alzheimer's disease; biomarkers; mitochondria; mitophagy; peripheral cells and fluids

DOI:  https://doi.org/10.1097/WCO.0000000000001457
Age Ageing. 2026 Feb 01. pii: afag022. [Epub ahead of print]55(2):

Association of mitochondrial oxidative capacity with physical fitness in ageing: the Baltimore longitudinal study of ageing.

Caterina Trevisan, Qu Tian, Kenneth W Fishbein, Sarah Church, Eleanor M Simonsick, Josephine M Egan, Stefano Volpato, Luigi Ferrucci.

   BACKGROUND: In younger individuals, fitness is mostly influenced by muscle mitochondrial oxidative phosphorylation (OxPhos) and cardiac output. However, compared with younger individuals, various impairments may also negatively affect fitness in older adults.
OBJECTIVE: To investigate the relationship of OxPhos with cardiorespiratory fitness, the energetic cost of walking and aerobic resilience with respect to age.
DESIGN: Cross-sectional.
SETTING: Population.
SUBJECTS: Six hundred and forty-nine Baltimore longitudinal study of ageing participants (mean age 64.5 years, 56.9% females).
METHODS: Muscle mitochondrial OxPhos was measured as phosphocreatine recovery rate (kPCr) through 31P magnetic resonance spectroscopy. Based on age- and sex-specific kPCr z-scores, we classified individuals with low (≤ -0.5 standard deviations [SD]), average (-0.5 to 0.5SD) and high (>0.5SD) OxPhos. Cardiorespiratory fitness was measured as peak oxygen consumption (MVO2 peak) during a treadmill testing. The energetic cost of usual pace walking was expressed as the average oxygen consumption per 100 metres. Aerobic resilience was the ratio between MVO2 peak and average VO2 during usual pace walking.
RESULTS: Participants with higher kPCr had 4.07 (95%CI: 2.88, 5.26) ml/kg/min higher MVO2 peak and 0.19 (95%CI: 0.06, 0.32) higher aerobic resilience than those with lower kPCr. The energetic cost of walking was greater by 0.84 (95% CI: 0.21, 1.47) ml/kg/100 m in those with high than low kPCr. A multiplicative interaction between age and kPCr was identified in the regressions predicting MVO2 peak and aerobic resilience (pinteraction = 0.01), with differences between OxPhos groups attenuating after age 70.
CONCLUSION: Muscle mitochondrial OxPhos contributes to interindividual variability in cardiorespiratory fitness, especially in young and middle adulthood.

Keywords:  ageing; cohort study; energetic cost of walking; mitochondria; older people; physical fitness

DOI:  https://doi.org/10.1093/ageing/afag022
Am J Clin Nutr. 2026 Jan 29. pii: S0002-9165(26)00019-5. [Epub ahead of print] 101210

Remission of impaired glucose tolerance by anthocyanin supplementation: a randomized, double-blind, placebo-controlled trial.

Lijun Yu, Senbate Amaliyati, Han Sun, Jie Dai, Yu Jiang, Zhe Li, Zhenhua Dong, Lina Zhao.

   BACKGROUND: Anthocyanin supplementation is a promising nutritional intervention for prediabetes, while the efficacy varies due to the heterogeneity of diseases. Efficacy of the anthocyanin supplementation in impaired glucose tolerance (IGT) is evaluated and possible mechanisms are further explored.
OBJECTIVE: This study aimed to investigate the effect of anthocyanin supplementation on pancreatic islet function in individuals with IGT.
METHODS: A 12-wk randomized, double-blind, placebo-controlled (anthocyanin 160 mg/day or placebo) trial was conducted with routine lifestyle guidance involving 68 IGT participants. The primary outcome was β-cell function: disposition index (DI). Secondary outcomes included other OGTT (oral glucose tolerance test)-derived indices, insulin sensitivity, anthropometric measures, and levels of skin advanced glycation end products (AGEs) measured by skin autofluorescence (SAF). Analyses followed intention-to-treat (ITT) principle.
RESULTS: For the primary outcome, there were no significant between-group differences in DI, with the adjusted mean differences of 61.3 (95% CI: -27.4, 150.0; P = 0.174). The IGT reversion rate [defined as 2-h OGTT glucose <7.8 mmol/L] was significantly higher in the anthocyanin group than in the placebo group (55.9 % compared with 29.4%, P = 0.013). In parallel with a greater improvement in Matsuda index, with an adjusted difference of 4.6 (95% CI: 2.5, 6.7; P = 0.003). Additionally, skin AGEs decreased significantly only in the anthocyanin group. The reduction in skin AGEs was positively correlated with the decrease in postprandial glucose area under the curve (AUC) (r = 0.302, P = 0.001) and negatively with improved Matsuda index (r = -0.344, P < 0.001).
CONCLUSIONS: Anthocyanin supplementation could significantly reverse IGT by improving insulin sensitivity. The reduction of skin AGEs by anthocyanins might play a critical role in the dietary management of IGT.
TRIAL REGISTRATION NUMBER: This trial was registered at the www.chictr.org.cn as ChiCTR2400079566.

Keywords:  Advanced Glycation End Products; Anthocyanins; Flavonoids; Impaired Glucose Tolerance; Insulin Sensitivity; Prediabetes; Randomized controlled trial

DOI:  https://doi.org/10.1016/j.ajcnut.2026.101210
Phytother Res. 2026 Feb 04.

Bridging Psychological Stress and Skin Cellular Aging: Flavonoids as a Dual-Action Therapeutic Strategy.

Marco Duarte, Sílvia Santos Pedrosa, P Raaj Khusial, Ana Raquel Madureira.

  Psychological stress (or simply "stress") is a major contributor to chronic disease worldwide, affecting 35% of the global population, including younger generations. Furthermore, it plays a significant role in human premature aging; hence, its detrimental effects on people's health compel us to comprehend and control the ways in which psychological stress impacts our bodies, including our skin. For example, flavonoids, a class of polyphenolic phytochemicals, are an important group of plant secondary metabolites and appear as a promising solution. These compounds exhibit a number of general biological activities, such as anti-inflammatory and antioxidant properties, as well as certain skin-specific ones, like wound healing, photoprotection, and the treatment of inflammatory and cancerous disorders associated with the skin. For this reason alone, flavonoids could be regarded as a promising solution. Further, these substances have demonstrated beneficial effects on the different hallmarks of aging, demonstrating their potential as anti-aging agents. They also have the ability to influence hormones linked to stress, which, considering their effects on skin health and aging mechanisms, seems to suggest that flavonoids may be effective ways to mitigate the negative effects of stress on premature skin aging. Therefore, this review seeks to demonstrate the potential of flavonoids as potential anti-aging agents for the skin, either by improving the so-called hallmarks of aging or by directly protecting the skin from external aggressors like UV radiation while reducing the negative effects of psychological stress and its known mediators.

Keywords:  flavonoids; hallmarks of aging; psychological stress; skin; stress mediators

DOI:  https://doi.org/10.1002/ptr.70239
Eur J Pharmacol. 2026 Feb 03. pii: S0014-2999(26)00123-8. [Epub ahead of print]1016 178641

Andrographolide analogues are agonists of the estrogen receptor alpha in vitro and in vivo.

Minghui Shu, Yi Duan, Yujuan Li, Pan Wang.

  Estrogen mediates diverse physiological and pathological processes through estrogen receptors (ERα and ERβ). Andrographolide analogues have broad pharmacological effects including anti-inflammation and antimicrobial, antiviral, and hepatoprotective activity. However, the direct targets of these andrographolide analogues are not clear yet. To evaluate whether andrographolide analogues deoxyandrographolide (DAGP), 14-deoxyandrographolide (14-DAGP) and 14-deoxy-11, 12-didehydroandrographolide (DDHA) could activate ERs, computational molecular docking, surface plasmon resonance (SPR) using purified ERα and ERβ ligand binding domain (LBD) proteins, luciferase reporter assay, and in vivo animal experiments were conducted. Molecular docking and SPR confirmed direct interaction of these analogues with ERα/β LBD. 14-DAGP and DDHA activated ERα (not ERβ) transcriptional activity in reporter assays, and stimulated endometrial cell proliferation in ovariectomized female mice and rats, indicating ERα agonism in vivo. 14-DAGP decreased total white adipose tissue (WAT) mass in ovariectomized rodents by activating ERα. In male mice, DDHA reduced UV-induced skin damage via ERα activation. This study identifies andrographolide analogues 14-DAGP and DDHA as a class of phytoestrogens in vitro and in vivo. They could reduce WAT mass and alleviate UV-induced skin damage in vivo through activation of ERα. Further studies are merited to reveal whether ERα mediated other pharmacological activities of andrographolide analogues.

Keywords:  12-Didehydroandrographolide; 14-Deoxy-11; 14-Deoxyandrographolide; Bioactive natural products; Deoxyandrographolide; Estrogen receptors (ER)

DOI:  https://doi.org/10.1016/j.ejphar.2026.178641
Transl Psychiatry. 2026 Feb 06.

Blood circulating cell-free mitochondrial DNA as a potential biomarker for major depressive disorder: a meta-analysis.

Yaman Zhang, Mingzhe Zhao, Shijie Song, Qiyuan Chen, Yi Meng, Xueli Yu, Wei Wei, Wei Deng, Wanjun Guo, Tao Li, Xueyu Qi.

BACKGROUND: Mitochondrial dysfunction has been implicated in major depressive disorder (MDD), but reliable, measurable biomarkers remain elusive. As a minimally invasive and quantifiable biomarker, circulating cell-free mitochondrial DNA (ccf-mtDNA) in blood offers potential for objective assessment of mitochondrial stress in MDD. However, evidence linking regarding the association between ccf-mtDNA levels and MDD is limited and inconsistent.
METHODS: We systematically searched eight databases, including PubMed, EMBASE, and major Chinese repositories. Thirteen studies with 1370 participants (837 individuals with MDD and 533 controls) were included per PRISMA guidelines. P-values were synthesized using the Lipták-Stouffer Z-score method. Sensitivity and fail-safe N analyses assessed the robustness of the findings and publication bias, and stratified analyses examined the effects of age, antidepressant use, and geographic region.
RESULTS: Across studies, elevated blood ccf-mtDNA levels were significantly associated with MDD (p = 0.013). Stratified analyses revealed stronger associations in older adults (≥60 years old; p = 0.0009), unmedicated patients (p = 4.99 × 10⁻⁶), and North American cohorts (p = 4.29 × 10⁻¹¹), but not in younger individuals (p = 0.83), medicated patients (p = 0.97), and Asian/European samples (p = 0.72, p = 0.99). Sensitivity analyses indicated moderate instability overall but confirmed data robustness in key subgroups.
CONCLUSIONS: This is the first meta-analysis to establish a significant link between elevated blood ccf-mtDNA and MDD, highlighting age and antidepressant exposure as critical modulators. These findings support the potential of blood ccf-mtDNA to serve as a biomarker for late-life and drug-naïve depression, with implications for objective diagnosis and personalized treatment.

DOI: https://doi.org/10.1038/s41398-026-03865-2
J Clin Endocrinol Metab. 2026 Jan 31. pii: dgag038. [Epub ahead of print]

Overnight wakefulness impairs next-day postprandial glucose in young women independent of sex hormones.

Pei Xue, Elisa M S Meth, Samira F M Noory, Viviana Rossi, Dina Motoshaleh, André P Pacheco, Heike Vogel, Diana A Nôga, Christian Benedict.

   CONTEXT: Estradiol and progesterone may influence glucose regulation, but it remains unclear whether ovarian hormone levels modulate night shift-induced impairments in glucose metabolism.
OBJECTIVE: To investigate the effects of a night shift-like schedule on next-morning fasting and postprandial glucose metabolism in reproductive-aged women.
METHODS: Fifty-two women with an HbA1c <5.7% completed a protocol consisting of one night of sleep and one night of wakefulness in a laboratory environment. After each night, fasting blood samples were collected to measure estradiol, progesterone, insulin, leptin, and adiponectin. Insulin resistance was estimated using HOMA-IR, and the leptin-to-adiponectin ratio (LAR)-a marker of fasting and postprandial insulin sensitivity-was calculated. Morning postprandial glucose responses were assessed using an oral glucose tolerance test (OGTT), and substrate utilization was measured via respiratory quotient (RQ) using indirect calorimetry. Linear mixed-effects models were used to test the effects of condition and the progesterone-to-estradiol (P/E) ratio on all outcomes.
RESULTS: Fasting glucose, HOMA-IR, and LAR did not differ between conditions. Post-OGTT blood glucose at 60 minutes (mean estimated difference: 0.58 mmol/L, p = 0.016) and peak glucose (0.42 mmol/L, p = 0.037) were higher following the night shift compared with sleep. The P/E ratio was not significantly associated with fasting or postprandial glucose. Pre-OGTT RQ was lower after the night shift (-0.029, p < 0.001), and adjusting for pre-OGTT RQ attenuated the post-OGTT glucose differences between conditions (p ≥ 0.097).
CONCLUSION: One night of wakefulness-as occurs in night shift work-impaired next-morning glucose tolerance in women, independent of ovarian hormone variation. Accordingly, choosing low-glycemic index foods for the first meal after a night shift may help reduce postprandial glucose excursions.

Keywords:  Female sex hormones; Indirect calorimetry; Night shift; Postprandial glucose metabolism

DOI:  https://doi.org/10.1210/clinem/dgag038
Redox Rep. 2026 Dec;31(1): 2622255

Urolithin A alleviates vascular remodeling through mitochondrial SIRT3-mediated SOD2 deacetylation and antioxidation in hypertensive rats.

Min Dai, Yi-Ming Wang, Hong-Ke Dong, Xiao-Yu Xu, Jing-Xiao Wang, Guo-Qing Zhu, Fen Zheng.

   OBJECTIVES: Urolithin A (UA) is a natural polyphenolic compound produced by gut bacteria. Vascular remodeling contributes to hypertension, and vascular smooth muscle cells (VSMCs) proliferation and migration are important processes in vascular remodeling.
METHODS: VSMCs were obtained from the thoracic aorta of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). Intraperitoneal injections of UA (50 mg/kg, every 2 days for 4 weeks) were performed in SHR.
RESULTS: UA attenuated proliferation and migration, reduced mitochondrial reactive oxygen species (mitoROS) levels, and increased SOD2 activity in VSMCs of SHR, which were prevented by SOD2 knockdown. UA promoted mitochondrial short-length SIRT3 (SL-SIRT3) production and SOD2 deacetylation. SIRT3 inhibitor 3-TYP abolished the effects of UA on SOD2 deacetylation, mitoROS levels and VSMCs proliferation and migration. Repeated intraperitoneal injection of UA every 2 days for 4 weeks attenuated vascular remodeling and hypertension, increased SL-SIRT3 levels and SOD2 activity, and reduced SOD2 acetylation and mitoROS levels in aorta and mesenteric arteries of SHR.
CONCLUSION: UA attenuates VSMCs proliferation and migration in SHR by increasing mitochondrial SL-SIRT3 level, and subsequent SOD2 deacetylation and mitoROS reduction in SHR. Long-term administration of UA attenuates vascular remodeling, hypertension and oxidative stress in SHR.

Keywords:  Urolithin A; hypertension; mitochondrial reactive oxygen species; superoxide dismutase 2; vascular remodeling; vascular smooth muscle cell

DOI:  https://doi.org/10.1080/13510002.2026.2622255
Maturitas. 2026 Jan 29. pii: S0378-5122(26)00034-4. [Epub ahead of print]206 108857

Cognitive function in relation to age at menopause: Insights from the English longitudinal study of aging.

Jiawei Zhai, Jinglei Huang, Yuou Chen, Ting Qiu, Huishu Liu.

   BACKGROUND: As global aging accelerates, cognitive decline is a major public health concern. Natural menopause, characterized by a sharp decline in endogenous estrogen, is a hypothesized modulator of long-term cognitive health, yet epidemiological evidence remains inconsistent. This study aimed to clarify the cross-sectional and longitudinal associations between age at natural menopause and cognitive function using data from the English Longitudinal Study of Aging (ELSA).
METHODS: This study included 3712 postmenopausal women aged ≥50 years from the English Longitudinal Study of Aging Wave 4 (2008-2009), with follow-up until Wave 9. The primary exposure was self-reported age at natural menopause. Cognitive function (memory, executive function, orientation) was synthesized into a global z-score. Multiple linear regression (cross-sectional) and linear mixed-effects models (longitudinal) were employed, with sequential adjustment for sociodemographic, lifestyle, and health-related covariates.
RESULTS: In these 3712 postmenopausal women, later age at menopause was consistently associated with better global cognitive function. Cross-sectionally, each additional year was linked to higher cognitive scores (β = 0.058, P < 0.001). Longitudinally, each year was associated with improved cognitive performance (β = 0.008, 95% CI 0.002-0.015, P = 0.014), with the latest menopause quartile (Q4) significantly outperforming the earliest (Q1) (β = 0.100, 95% CI 0.010-0.189, P = 0.030). Subgroup and sensitivity analyses corroborated the robustness of the primary findings.
CONCLUSION: This study found that a later age at menopause correlates with improved cognitive abilities.

Keywords:  Age at menopause; Cognitive function; English longitudinal study of aging

DOI:  https://doi.org/10.1016/j.maturitas.2026.108857