bims-mistre 2025-09-14 papers

bims-mistre

Biomed News

on Mito stress

Issue of 2025–09–14
sixteen papers selected by
Ellen Siobhan Mitchell, MitoQ

Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives.
Mitochondrial dysfunction in depression: Mechanisms and targeted therapy strategies.
Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.
Mitochondrial Physiology and Beyond: Mechanistic Insights into Kaempferol Actions.
Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.
Advances and prospects of ergothioneine in the treatment of cognitive frailty.
Are an Aging Gut and a Decrease in Butyrate Production the Reasons for Atherosclerosis?
Alterations of telomere length and mitochondrial DNA copy number in depressive adolescents with non-suicidal self-injury.
Epigenetic Age Acceleration and Cardiometabolic Biomarkers in Response to Weight-Loss Dietary Interventions Among Obese Individuals: The MACRO Trial.
Selective Autophagy in Type 2 Diabetes-Associated Cognitive Dysfunction: Insightful Mechanisms and Therapies.
Interplay of Glut1 alteration and Alzheimer's disease: A narrative review on glucose transport and energy metabolism.
Adaptations in Mitochondrial Function Induced by Exercise: A Therapeutic Route for Treatment-Resistant Depression.
Emerging strategies, applications and challenges of targeting NAD+ in the clinic.
Slowing down the clock on ovarian aging-does the ovary hold the secret to the fountain of youth?
Improvement Effect and Mechanism of Hydroxytyrosol on Skin Aging Induced Advanced Glycation End Products.
Epigallocatechin-3-Gallate from Green Tea Reduces Vascular Aging and Endothelial Cell Senescence by Modifying Autophagy and Ferroptosis through the Sirtuin 1 Signaling Pathway.

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Sep 09. pii: S0278-5846(25)00245-3. [Epub ahead of print] 111491

Targeting mitochondrial dysfunction in Alzheimer's disease: New findings and perspectives.

Authors Jana Hroudová, Zdeněk Fišar.

  Alterations in mitochondrial energy metabolism, impaired processes of mitochondrial dynamics and mitophagy have recently been identified as important contributors to the pathophysiology of Alzheimer's disease (AD). Genetic predispositions and defects in mitochondrial metabolism, particularly within the electron transport chain of the oxidative phosphorylation system, have been linked to the pathology of intracellular and extracellular amyloid-beta (Aβ) and tau protein. This review summarizes the current molecular background of AD and explains the relationships between genetic factors, impaired energy metabolism, and the formation of pathological proteins. It highlights altered mitochondrial dynamics, impaired mitochondrial signaling, mitophagy, neuroinflammation, and apoptosis. Based on these findings, the review discusses mitochondrial biomarkers and novel molecules targeting mitochondrial dysfunction in the pathophysiology of AD.

Keywords:  Alzheimer's disease; Amyloid beta; Energy metabolism; Mitochondria; Mitophagy

DOI:  https://doi.org/10.1016/j.pnpbp.2025.111491
Asian J Psychiatr. 2025 Sep 05. pii: S1876-2018(25)00337-5. [Epub ahead of print]112 104694

Mitochondrial dysfunction in depression: Mechanisms and targeted therapy strategies.

Xue Xia, Kaiqing Li, Baiyi Jiang, Wei Zou, Long Wang.

  Major depressive disorder (MDD) is a severe mental illness with complex pathophysiology. Growing evidence highlights mitochondrial dysfunction as a key player in MDD, influencing neuroinflammation, synaptic plasticity, and energy metabolism. This review summarizes recent advances in understanding how mitochondrial defects-including mtDNA mutations, impaired mitophagy, disrupted dynamics, altered biogenesis, and metabolic dysregulation-contribute to depressive pathogenesis. We also evaluate mitochondria-targeted therapeutic strategies, encompassing both pharmacological agents (e.g., antioxidants, CoQ10, NAD+ precursors, SSRIs, and natural compounds) and non-pharmacological interventions (e.g., exercise, ketogenic diet, photobiomodulation, and electroacupuncture). Importantly, we emphasize the interplay between mitochondrial processes and the need to balance anabolic and catabolic functions. While preclinical results are promising, further clinical translation is essential. This review underscores mitochondrial health as a central theme in MDD research and therapy development.

Keywords:  Major depressive disorder; Mitochondria-targeted therapy; Mitochondrial DNA; Mitochondrial dysfunction; Neuroplasticity

DOI:  https://doi.org/10.1016/j.ajp.2025.104694
EMBO J. 2025 Sep 08.

Mammalian mitohormesis: from mitochondrial stressors to organismal benefits.

Amanda L Gunawan, Irene Liparulo, Andreas Stahl.

  A variety of stressors, including environmental insults, pathological conditions, and transition states, constantly challenge cells that, in turn, activate adaptive responses to maintain homeostasis. Mitochondria have pivotal roles in orchestrating these responses that influence not only cellular energy production but also broader physiological processes. Mitochondria contribute to stress adaptation through mechanisms including induction of the mitochondrial unfolded protein response (UPRmt) and the integrated stress response (ISR). These responses are essential for managing mitochondrial proteostasis and restoring cellular function, with each being tailored to specific stressors and cellular milieus. While excessive stress can lead to maladaptive responses, mitohormesis refers to the beneficial effects of low-level mitochondrial stress. Initially studied in invertebrates and cell cultures, recent research has expanded to mammalian models of mitohormesis. In this literature review, we describe the current landscape of mammalian mitohormesis research and identify mechanistic patterns that result in local, systemic, or interorgan mitohormesis. These investigations reveal the potential for targeting mitohormesis for therapeutic benefit and can transform the treatment of diseases commonly associated with mitochondrial stress in humans.

Keywords:  Integrated Stress Response; Mammalian Models; Mitochondrial Retrograde Signaling; Mitochondrial Unfolded Protein Response (UPRmt); Mitohormesis

DOI:  https://doi.org/10.1038/s44318-025-00549-3
Chem Biol Interact. 2025 Sep 10. pii: S0009-2797(25)00373-4. [Epub ahead of print] 111743

Mitochondrial Physiology and Beyond: Mechanistic Insights into Kaempferol Actions.

Marcos Roberto de Oliveira.

  Kaempferol (KAE), a dietary flavonoid, has emerged as a potent modulator of mitochondrial physiology, exerting multifaceted actions on bioenergetics, redox balance, mitochondrial dynamics, biogenesis, and quality control. Thus, the aim of this review is to discuss the effects promoted by KAE on mitochondrial physiology from a mechanistic view. Data from diverse in vitro and in vivo models indicate that KAE enhances mitochondrial function by stimulating ATP production, preserving membrane potential, promoting calcium uptake, and increasing the activity or expression of oxidative phosphorylation (OXPHOS) complexes. KAE also activates key signaling pathways, including phosphatidylinositol 3-kinase (PI3K)/Akt, adenosine monophosphate-activated protein kinase/ peroxisome proliferator-activated receptor gamma coactivator 1-α (AMPK/PGC-1α), and nuclear factor erythroid 2-related factor 2 (Nrf2), contributing to mitochondrial biogenesis, antioxidant defense, and cellular survival. In parallel, KAE modulates mitochondrial dynamics by inhibiting fission and promoting fusion, while also inducing mitophagy, particularly under neurotoxic or ischemic conditions. However, at elevated concentrations, KAE may disrupt mitochondrial homeostasis by inhibiting Complex V activity, inducing oxidative stress, and depolarizing mitochondria, suggesting a concentration- and context-dependent duality. Furthermore, nanotechnology-based delivery systems targeting KAE to mitochondria have demonstrated enhanced therapeutic potential in preclinical disease models, reinforcing its translational relevance. Collectively, these findings support KAE as a promising candidate for mitochondrial-targeted interventions in diseases characterized by mitochondrial dysfunction. Nonetheless, mechanistic gaps remain regarding its impact on mitochondrial protein acetylation, quality control signaling, and the long-term effects of chronic exposure. Future research should focus on dissecting these pathways and validating the therapeutic window of KAE in clinical settings.

Keywords:  kaempferol; mitochondrial biogenesis; mitochondrial dynamics; mitochondrial function; mitophagy; redox signaling

DOI:  https://doi.org/10.1016/j.cbi.2025.111743
Autophagy. 2025 Sep 13.

Urolithin a modulates inter-organellar communication via calcium-dependent mitophagy to promote healthy ageing.

Antonis Roussos, Katerina Kitopoulou, Fivos Borbolis, Christina Ploumi, Despoina D Gianniou, Zhiquan Li, Haijun He, Eleni Tsakiri, Helena Borland, Ioannis K Kostakis, Martina Samiotaki, Ioannis P Trougakos, Vilhelm A Bohr, Konstantinos Palikaras.

  Mitochondrial dysfunction and impaired mitophagy are hallmarks of aging and age-related pathologies. Disrupted inter-organellar communication among mitochondria, endoplasmic reticulum (ER), and lysosomes, further contributes to cellular dysfunction. While mitophagy has emerged as a promising target for neuroprotection and geroprotection, its potential to restore age-associated defects in organellar crosstalk remains unclear. Here, we show that mitophagy deficiency deregulates the morphology and homeostasis of mitochondria, ER and lysosomes, mirroring age-related alterations. In contrast, urolithin A (UA), a gut-derived metabolite and potent mitophagy inducer, restores inter-organellar communication via calcium signaling, thereby, promoting mitophagy, healthspan and longevity. Our multi-omic analyses reveal that UA reorganizes ER, mitochondrial and lysosomal networks, linking inter-organellar dynamics to mitochondrial quality control. In C. elegans, UA induces calcium release from the ER, enhances lysosomal activity, and drives DRP-1/DNM1L/DRP1-mediated mitochondrial fission, culminating in efficient mitophagy. Calcium chelation abolishes UA-induced mitophagy, blocking its beneficial impact on muscle function and lifespan, underscoring the critical role of calcium signaling in UA's geroprotective effects. Furthermore, UA-induced calcium elevation activates mitochondrial biogenesis via UNC-43/CAMK2D and SKN-1/NFE2L2/Nrf2 pathways, which are both essential for healthspan and lifespan extension. Similarly, in mammalian cells, UA increases intracellular calcium, enhances mitophagy and mitochondrial metabolism, and mitigates stress-induced senescence in a calcium-dependent manner. Our findings uncover a conserved mechanism by which UA-induced mitophagy restores inter-organellar communication, supporting cellular homeostasis and organismal health.

Keywords:  Calcium; ER; cellular senescence; geroprotection; lysosome; mitochondria

DOI:  https://doi.org/10.1080/15548627.2025.2561073
Ann Med. 2025 Dec;57(1): 2555742

Advances and prospects of ergothioneine in the treatment of cognitive frailty.

Arjun M M I Gede, Qingxin Gu, Piyaporn Phukhatmuen, Jian Xiong, Shuang Zhang, Mingliang Yi, Sitthichock Vadphimai, Wenchuan Qi.

   BACKGROUND: To review the biological functions of ergothioneine (ERGO), its correlation with plasma levels in cognitive frailty, and research progress in treating frailty and cognitive impairment, with the aim of providing a reference for ERGO application in cognitive frailty treatment.
METHODS: A comprehensive review of existing literature on ERGO's chemical structure, sources, antioxidant and anti-inflammatory effects, and its role in cognitive frailty was conducted. Clinical trial data and metabolomic studies were also analyzed to understand ERGO's therapeutic potential.
RESULTS: ERGO, a naturally occurring antioxidant, exhibits strong antioxidant, anti-inflammatory, and immunomodulatory activities. Age-related declines in plasma ERGO levels are observed, particularly in individuals with cognitive impairment. Metabolomic analyses confirm ERGO's beneficial effects on cognition and memory. Preclinical studies demonstrate ERGO's capacity to enhance cognitive function and neuronal health through oxidative stress reduction and neuroprotection.
CONCLUSION: Preclinical studies have underscored ERGO's potent antioxidant, anti-inflammatory, and neuroprotective effects, suggesting its potential as a therapeutic agent for cognitive frailty. However, the translation of these findings into clinical benefits necessitates validation through well-designed clinical trials. While existing evidence is promising, suggesting ERGO as a viable complementary intervention, comprehensive and rigorous studies are imperative to establish its clinical efficacy and safety in managing cognitive frailty.

Keywords:  Antioxidant; clinical trials; cognitive frailty; ergothioneine; neuroprotective

DOI:  https://doi.org/10.1080/07853890.2025.2555742
Int J Mol Sci. 2025 Aug 26. pii: 8276. [Epub ahead of print]26(17):

Are an Aging Gut and a Decrease in Butyrate Production the Reasons for Atherosclerosis?

Leon M T Dicks.

  Atherosclerosis (AS) is directly linked to the aging and damage of endothelial cells (ECs). As ECs and vascular smooth muscle cells (VSMCs) age, more autocrine and paracrine signals are released, extending a vicious cycle of tissue aging and physiological dysfunction. The recruitment of immune cells to inflamed arteries, including coronary arteries, and an increase in the uptake of oxidised low-density lipoprotein (ox-LDL) by macrophages (foam cells) onto the tunica intima (intima) of coronary arteries restrict blood flow. The inability of aging and damaged ECs to accommodate vast changes in signalling molecules, many produced by gut microbiota, leads to a range of anatomical and physiological arterial anomalies. These include degradation of cardiovascular membranes, fibrosis, calcification, plaque formation, and an increasingly dysfunctional immune system. Changes in the gut microbiome of the elderly have a direct effect on the immune response, as the signalling molecules produced by gut microbiota target specific receptors on inflamed arteries. This review summarizes the anatomical and physiological changes associated with the aging of coronary arteries and emphasizes the conditions leading to AS. The importance of butyrate-producing gut microbiota in preventing AS, especially in the elderly, is discussed.

Keywords:  aging; atherosclerosis; gut microbiota

DOI:  https://doi.org/10.3390/ijms26178276
J Affect Disord. 2025 Sep 08. pii: S0165-0327(25)01710-0. [Epub ahead of print] 120268

Alterations of telomere length and mitochondrial DNA copy number in depressive adolescents with non-suicidal self-injury.

Dong-Ni Wen, Jia-Hui Hu, Ting Ji, Xing-Yu Xiao, Chengcheng Xin Huang, Ji-Fan Zhang, Wei-Biao Feng, Shuo Zheng, Zi-Yi Xiong, Cai-Lan Hou.

   BACKGROUND: NSSI among adolescents is highly prevalent and serves as a significant indicator of subsequent suicidal ideation and behaviors. Recent studies have demonstrated a connection between accelerated cellular aging and a range of psychiatric conditions. The present study explored whether depressive adolescents with NSSI exhibited alterations in telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), both critical markers of cellular aging.
METHODS: The study comprised 70 depressive adolescents with NSSI (84.3 % female) and 34 depressive adolescents without NSSI (61.8 % female). The TL and mtDNAcn were determined by calculating the ratio of telomere repeats to the single-copy gene β-globin, or by measuring the relative quantity of mtDNA compared to β-globin.
RESULTS: In this study, the NSSI group demonstrated significantly shorter TL than the non-NSSI group (P < 0.01). This difference persisted after controlling for age, family history, sex, suicidality, childhood maltreatment, depressive symptoms, and psychotic symptoms (P = 0.005). Furthermore, regression analysis showed that TL was considerably shorter in the female NSSI group than in the non-NSSI group after adjusting for age, family history, suicidality, childhood maltreatment, depressive symptoms, and psychotic symptoms (P < 0.001). After controlling for these variables, mtDNAcn was markedly reduced in the male NSSI group compared to the non-NSSI group (P < 0.001).
CONCLUSIONS: This work is, to our knowledge, the first to demonstrate that NSSI correlates with alterations in TL and mtDNAcn. These findings suggest that molecular pathways associated with aging may play a crucial role in the pathogenesis of NSSI.

Keywords:  Adolescent depression; Mitochondrial DNA copy number; NSSI; Telomere length

DOI:  https://doi.org/10.1016/j.jad.2025.120268
Aging Cell. 2025 Sep 08. e70224

Epigenetic Age Acceleration and Cardiometabolic Biomarkers in Response to Weight-Loss Dietary Interventions Among Obese Individuals: The MACRO Trial.

Minghao Kou, Xiang Li, Yoriko Heianza, Kirsten Dorans, Lydia Bazzano, Lu Qi.

  Epigenetic clocks have emerged as promising biomarkers of aging, but their responsiveness to lifestyle interventions and relevance for short-term changes in cardiometabolic health remain uncertain. In this study, we examined the associations between three epigenetic aging measures (DunedinPACE, PCPhenoAge acceleration, and PCGrimAge acceleration) and a broad panel of cardiometabolic biomarkers in 144 obese participants from the MACRO trial, a 12-month weight-loss dietary intervention comparing low-carbohydrate and low-fat diets. At pre-intervention baseline, DunedinPACE was significantly associated with several cardiometabolic biomarkers (FDR [false discovery rate] < 0.05), including insulin, homeostatic model assessment for insulin resistance (HOMA-IR), total cholesterol, high-density lipoprotein cholesterol, C-reactive protein, adiponectin, and ghrelin. These associations were substantially attenuated following the intervention, with only CRP and adiponectin remaining significant. Changes in epigenetic aging measures were not significantly associated with changes in biomarkers, nor did they mediate the effects of weight loss. Our findings highlight DunedinPACE as a sensitive biomarker of cardiometabolic health in adults with obesity but raise questions about the utility of epigenetic clocks as causal targets in short-term lifestyle interventions. While caloric restriction may attenuate some phenotypic manifestations of biological aging, short-term changes in epigenetic aging measures may not fully reflect underlying cardiometabolic changes. These results underscore the need for caution in interpreting epigenetic aging as a modifiable intervention target.

Keywords:  DNA methylation; aging; cardiometabolic health; dietary intervention

DOI:  https://doi.org/10.1111/acel.70224
Pharmacol Res. 2025 Sep 10. pii: S1043-6618(25)00372-X. [Epub ahead of print] 107947

Selective Autophagy in Type 2 Diabetes-Associated Cognitive Dysfunction: Insightful Mechanisms and Therapies.

Li Luo, Mengxin Que, Lian Zeng, Xuan Wang, Tianning Sun, Zhiqiang Zhou, Yilin Zhao, Shiyong Li, Ailin Luo.

  Type 2 diabetes-associated cognitive dysfunction (TDACD) is an escalating yet underestimated global health challenge, reflecting a complex convergence of metabolic dysregulation and neurodegenerative pathogenesis. Despite increasing concern, its underlying neuropathogenesis remains partially elucidated. It should be noted that T2DM and neurodegenerative diseases exhibit a high degree of overlap in pathological mechanisms, including impaired insulin signaling, neuroinflammation, oxidative stress, mitochondrial dysfunction, blood-brain barrier disruption, and autophagy dysregulation, and these shared mechanisms constitute the neuropathogenesis of TDACD. Accumulating findings have identified selective autophagy as a pivotal mechanism in preserving neuronal integrity and mitigating cellular stress under diabetic conditions. Distinct from non-selective autophagy, selective autophagy enables the precise degradation of specific subcellular substrates, mitochondria, endoplasmic reticulum, lysosomes, ferritin, lipid droplets, and glycogen, each of which contributes uniquely to neuroprotection or pathology. This review comprehensively synthesizes current mechanistic insights into how these selective autophagic subtypes modulate neural function in the context of TDACD, underscoring their respective roles in mitochondrial quality control, ER stress resolution, iron homeostasis, lipid metabolism, and energy regulation. Furthermore, we summarize potential therapeutic strategies targeting specific autophagic pathways, offering a novel perspective for the prevention or treatment of TDACD. By positioning selective autophagy as a critical interface between neurodegeneration and metabolic stress responses, this review proposes a pathway-specific and precision-based framework for mitigating cognitive decline in type 2 diabetes.

Keywords:  Cognitive dysfunction; ER-phagy; Ferritinophagy; Lipophagy; Mitophagy; Neurodegeneration; Selective autophagy; Type2 diabetes mellitus

DOI:  https://doi.org/10.1016/j.phrs.2025.107947
J Alzheimers Dis. 2025 Sep 12. 13872877251377793

Interplay of Glut1 alteration and Alzheimer's disease: A narrative review on glucose transport and energy metabolism.

Sodiq Fakorede, Toheeb Ayodeji Sodiq, Abayomi Oyeyemi Ajagbe, Adewale James Adeleke, Okeoghene Marcel Edafetanure-Ibeh, Taiwo Ayomide Awobona, Abdullahi Tunde Aborode.

  Alzheimer's disease (AD) is a prevalent neurodegenerative disorder primarily affecting the aging population, characterized by progressive cognitive decline. Traditional models of AD pathogenesis, including the amyloid cascade and tau hypotheses, have not yielded definitive therapeutic breakthroughs. Emerging research suggests that metabolic dysfunction, particularly in glucose transport, plays a central role in AD progression. The glucose transporter 1 (GLUT1), which facilitates glucose entry across the blood-brain barrier, is crucial for maintaining brain energy metabolism. Studies have shown reduced GLUT1 expression in AD brains, impairing cerebral glucose uptake and contributing to neuronal dysfunction and neurodegeneration. This review synthesizes current evidence on the interplay between GLUT1 alteration and AD, highlighting how disruptions in glucose transport can exacerbate the disease's neuropathological features, including amyloid and tau pathologies. Furthermore, we explore potential therapeutic strategies aimed at restoring GLUT1 function, such as gene therapy, ketogenic diets, and small molecules that enhance GLUT1 expression. These approaches may offer promising avenues to mitigate the metabolic dysfunction driving AD and improve patient outcomes. This work underscores the importance of integrating metabolic insights into AD research to develop innovative therapeutic targets and interventions.

Keywords:  Alzheimer's disease; GLUT1; brain energy metabolism; glucose transport; neurodegeneration

DOI:  https://doi.org/10.1177/13872877251377793
Int J Mol Sci. 2025 Sep 06. pii: 8697. [Epub ahead of print]26(17):

Adaptations in Mitochondrial Function Induced by Exercise: A Therapeutic Route for Treatment-Resistant Depression.

Arnulfo Ramos-Jiménez, Mariazel Rubio-Valles, Javier A Ramos-Hernández, Everardo González-Rodríguez, Verónica Moreno-Brito.

  Mitochondrial dysfunction is a key factor in the pathophysiology of major depressive disorder (MDD) and treatment-resistant depression (TRD), connecting oxidative stress, neuroinflammation, and reduced neuroplasticity. Physical exercise induces specific mitochondrial changes linked to improvements in mental health. The aim of this paper was to examine emerging evidence regarding the effects of physical exercise on mitochondrial function and treatment-resistant depression, highlighting the clinical importance of the use of mitochondrial biomarkers to personalize exercise prescriptions for patients with depression, particularly those who cannot tolerate standard treatments. Physical exercise improves mitochondrial function, enhances biogenesis and neuroplasticity, and decreases oxidative stress and neuroinflammation. Essential signaling pathways, including brain-derived neurotrophic factor, AMP-activated protein kinase, active peroxisome proliferator-activated receptor-γ coactivator-1α, and Ca2+/calmodulin-dependent protein kinase, support these effects. Most studies have concentrated on the impact of low- and moderate-intensity aerobic exercise on general health. However, new evidence suggests that resistance exercise and high-intensity interval training also promote healthy mitochondrial adaptations, although the specific exercise intensity required to achieve this goal remains to be determined. There is strong evidence that exercise is an effective treatment for MDD, particularly for TRD, by promoting specific mitochondrial adaptations. However, key gaps remain in our understanding of the optimal exercise dose and which patient subgroups are most likely to benefit from it (Graphical Abstract).

Keywords:  behavioral stress; mitochondrial dynamics; mood disorders; neurophysiological disturbances; neuroplasticity; physical exercise; sedentarism; treatment-resistant depression

DOI:  https://doi.org/10.3390/ijms26178697
Nat Aging. 2025 Sep 09.

Emerging strategies, applications and challenges of targeting NAD+ in the clinic.

Jianying Zhang, He-Ling Wang, Sofie Lautrup, Hilde Loge Nilsen, Jonas T Treebak, Leiv Otto Watne, Geir Selbæk, Lindsay E Wu, Torbjørn Omland, Eija Pirinen, Tin Cho Cheung, Jun Wang, Mathias Ziegler, Ole-Bjørn Tysnes, Rubén Zapata-Pérez, Santina Bruzzone, Carles Canto, Michela Deleidi, Georges E Janssens, Riekelt H Houtkooper, Morten Scheibye-Knudsen, Masaya Koshizaka, Koutaro Yokote, Eric Verdin, Vilhelm A Bohr, Charalampos Tzoulis, David A Sinclair, Evandro Fei Fang.

Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response.

DOI: https://doi.org/10.1038/s43587-025-00947-6
Geroscience. 2025 Sep 10.

Slowing down the clock on ovarian aging-does the ovary hold the secret to the fountain of youth?

Paula Benny, Xi Yuan, Qian Yang, Jorge Chavarro, Brian Kennedy, Zhongwei Huang.

  In the past century, the human Lifespan has doubled. However, this is not equivalent to Healthspan which refers to the number of years spent healthy and free from disease. Women have an additional level of complexity on the path to optimal healthspan where health resilience dramatically decreases following menopause and this is due to their ovaries aging by midlife. It still remains elusive on why and how the ovaries in women, albeit their distinct and vital reproductive functions, start to age before any other organs. Following menopause, women are at increased risks of age-associated chronic diseases such as cardiometabolic disease, osteoporosis, sarcopenia, frailty, and neurocognitive decline. By preserving reproductive longevity through targeting the ovary as the organ to rejuvenate in women, optimal healthspan could be obtained in women. Interestingly, population studies have shown that women who conceive naturally and give birth at advanced reproductive ages are demonstrated to have superior postmenopausal longevity. Correspondingly, men Lived longer with a sister reproducing after 45 years of age in natural fertility conditions, suggesting that late female fertility and slow somatic aging may be promoted by the same genetic variants. Causal inference analysis showed a link between increased reproductive lifespan (prolonged ovarian lifespan or later age at natural menopause) and a reduction of diseases such as diabetes and osteoporosis. Essentially, fewer ovarian follicles and shorter ovarian lifespan were associated with poorer health later in life. Therefore, innovative ways to understand and target the ovaries in women for gero-protection have the potential to avert aging diseases triggered by the female menopause. Our narrative review aims to integrate existing information from systemic and reproductive aging from preclinical and human studies to devise novel methodologies to avert ovarian aging which could potentially improve the health trajectory in aging women. Similar strategies can be applied to men to achieve healthy longevity in the population. While there are certain things one has little control over, such as genetics and the inevitable reduction of reproductive hormone levels over time, there are modifiable risk factors which can be targeted to preserve reproductive longevity by uniquely targeting the ovary especially in modifying and improving the ovarian microenvironment to ensure survival of the ovarian follicles which determine true reproductive lifespan and healthspan. This can be achieved by modifying diet, sleep patterns, and exercise and limiting toxin exposure to ensure optimal ovarian health, through healthy and functional ovarian follicles, which could bring us a step closer to enhancing women's healthspan and human longevity.

Keywords:  Aging; Ovarian biology; Quality of life; Reproductive longevity; Women’s health

DOI:  https://doi.org/10.1007/s11357-025-01876-3
Nutrients. 2025 Aug 29. pii: 2810. [Epub ahead of print]17(17):

Improvement Effect and Mechanism of Hydroxytyrosol on Skin Aging Induced Advanced Glycation End Products.

Rui Fan, Yuxin Ma, Meng Sun, Haohao Zhang, Yaxin Han, Junbo Wang, Wenli Zhu, Zhaofeng Zhang.

  Objectives: Skin aging, often accelerated by dietary advanced glycation end products (AGEs), poses both cosmetic and health challenges. This study explores the protective effects of hydroxytyrosol (HT), a potent antioxidant found in olives, against AGEs-induced skin aging in mice. Methods: A total of forty-eight 8-month-old specific pathogen-free (SPF) male C57BL/6J mice were randomly assigned to one of four groups: control, model, low-dose hydroxytyrosol (HT25), and high-dose hydroxytyrosol (HT50). An additional group of six 6-week-old SPF male C57BL/6J mice served as the youth group. The experimental period lasted 16 weeks. Following the intervention, skin, serum, and ileum samples were collected. Results: The results demonstrated that HT50 significantly increased skin moisture, epidermal thickness, and dermal thickness (p < 0.05). HT50 also significantly elevated hydroxyproline levels as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in the skin while reducing malondialdehyde (MDA) content (p < 0.05). Furthermore, HT50 significantly reduced the levels of interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) (p < 0.05). Regarding intestinal integrity, hydroxytyrosol intervention (either HT25 or HT50) significantly increased the positive staining ratios of zonula occludens-1 (ZO-1) and occludin in the ileum (p < 0.05). Conclusions: HT improves skin hydration, thickness, and collagen levels while reducing oxidative stress and inflammation. Notably, HT also enhances intestinal barrier function, suggesting a role for the gut-skin axis. These findings highlight HT's potential as a natural intervention for skin aging.

Keywords:  advanced glycation end products; hydroxytyrosol; inflammatory response; oxidative; skin aging

DOI:  https://doi.org/10.3390/nu17172810
ACS Omega. 2025 Sep 02. 10(34): 38740-38752

Epigallocatechin-3-Gallate from Green Tea Reduces Vascular Aging and Endothelial Cell Senescence by Modifying Autophagy and Ferroptosis through the Sirtuin 1 Signaling Pathway.

Yingjie Zhang, Tianhu Wang, Linghuan Wang, Zhiyi Fang, Tingting Lu, Sijia Chen, Jin Yan, Cheng Qin, Xiaoying Shen, Na Kang, Lei Tian, Feng Cao.

Vascular aging is a major risk factor for cardiovascular diseases (CVDs) in the older individuals. Epigallocatechin-3-gallate (EGCG), the primary active compound in green tea, exhibits cardiovascular protective effects. However, its effect and the underlying mechanism of the same on vascular aging remain unclear. Herein, doxorubicin (DOX) was employed to develop an endothelial cell senescence model. In vitro results indicated that EGCG alleviates endothelial cell senescence by promoting autophagy and inhibiting ferroptosis, supported by Western blot analysis. In vivo animal studies revealed a significant decrease in aortic senescence-associated β-galactosidase (SA-β-gal) positive staining and pulse wave velocity (PWV) in the EGCG group compared with that in the control group (p < 0.001), indicating that EGCG can significantly attenuate vascular aging in mice. Multiple lines of evidence suggest that EGCG alleviates vascular aging by activating sirtuin 1 (SIRT1), which promotes autophagy and inhibits ferroptosis.

DOI: https://doi.org/10.1021/acsomega.5c03880