bims-caglex Biomed News
on Cellular aging and life extension
Issue of 2025–03–30
48 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño



  1. Nat Commun. 2025 Mar 24. 16(1): 2878
      Accumulated senescent cells during the aging process are a key driver of functional decline and age-related disorders. Here, we identify ganoderic acid A (GAA) as a potent anti-senescent compound with low toxicity and favorable drug properties through high-content screening. GAA, a major natural component of Ganoderma lucidum, possesses broad-spectrum geroprotective activity across various species. In C. elegans, GAA treatment extends lifespan and healthspan as effectively as rapamycin. Administration of GAA also mitigates the accumulation of senescent cells and physiological decline in multiple organs of irradiation-stimulated premature aging mice, natural aged mice, and western diet-induced obese mice. Notably, GAA displays a capability to enhance physical function and adapts to conditional changes in metabolic demand as mice aged. Mechanistically, GAA directly binds to TCOF1 to maintain ribosome homeostasis and thereby alleviate cellular senescence. These findings suggest a feasible senotherapeutic strategy for protecting against cellular senescence and age-related pathologies.
    DOI:  https://doi.org/10.1038/s41467-025-58188-5
  2. Front Med. 2025 Mar 22.
      The quest to decipher the determinants of human longevity has intensified with the rise in global life expectancy. Long-lived individuals (LLIs), who exceed the average life expectancy while delaying age-related diseases, serve as a unique model for studying human healthy aging and longevity. Longevity is a complex phenotype influenced by both genetic and non-genetic factors. This review paper delves into the genetic, epigenetic, metabolic, immune, and environmental factors underpinning the phenomenon of human longevity, with a particular focus on LLIs, such as centenarians. By integrating findings from human longevity studies, this review highlights a diverse array of factors influencing longevity, ranging from genetic polymorphisms and epigenetic modifications to the impacts of diet and physical activity. As life expectancy grows, understanding these factors is crucial for developing strategies that promote a healthier and longer life.
    Keywords:  age-related diseases; centenarians; long-lived individuals; longevity; longevity factors
    DOI:  https://doi.org/10.1007/s11684-024-1120-4
  3. Aging Cell. 2025 Mar 24. e14465
      Caloric restriction is associated with slow aging in model organisms. Additionally, some drugs have also been shown to slow aging in rodents. To better understand metabolic mechanisms that are involved in increased lifespan, we analyzed metabolomic differences in six organs of 12-month-old mice using five interventions leading to extended longevity, specifically caloric restriction, 17-α estradiol, and caloric restriction mimetics rapamycin, canagliflozin, and acarbose. These interventions generally have a stronger effect in males than in females. Using Jonckheere's trend test to associate increased average lifespans with metabolic changes for each sex, we found sexual dimorphism in metabolism of plasma, liver, gastrocnemius muscle, kidney, and inguinal fat. Plasma showed the strongest trend of differentially expressed compounds, highlighting potential benefits of plasma in tracking healthy aging. Using chemical set enrichment analysis, we found that the majority of these affected compounds were lipids, particularly in male tissues, in addition to significant differences in trends for amino acids, which were particularly apparent in the kidney. We also found strong metabolomic effects in adipose tissues. Inguinal fat exhibited surprising increases in neutral lipids with polyunsaturated side chains in male mice. In female mice, gonadal fat showed trends proportional to lifespan extension effect across multiple lipid classes, particularly phospholipids. Interestingly, for most tissues, we found similar changes induced by lifespan-extending interventions to metabolomic differences between untreated 12-month-old mice and 4-month-old mice. This finding implies that lifespan-extending treatments tend to reverse metabolic phenotypes to a biologically younger stage.
    Keywords:  aging; drugs; lipids; longevity regulation; mass spectrometry
    DOI:  https://doi.org/10.1111/acel.14465
  4. Exp Gerontol. 2025 Mar 25. pii: S0531-5565(25)00067-1. [Epub ahead of print]204 112738
      Collagen loss is one of the major contributor to signs of skin aging such as dryness, roughness, and wrinkle formation, which is closely linked to a decline in the amount of proline produced in mitochondria. Melatonin has been shown to improve several clinical signs of skin aging, while the mechanism is unclear. In our study, we found that mitophagy, proline synthesis key enzyme NADK2 and proline and collagen levels were significantly reduced, while oxidative stress levels increased in aging skin, and melatonin supplementation could effectively up-regulate mitophagy level and restore proline synthesis and further improved skin aging. However, proline supplementation could also exert an anti-aging effect, while it had no effect on the mitochondrial dysfunction. Moreover, our study indicated that melatonin enters the cell by binding to the MT1 receptor and then enters the mitochondria via the PEPT1 transporter to exert its mitochondrial protective effects. This study helps to elucidate the mechanism of mitochondrial dysfunction-induced skin aging, and provides new theoretical guidance for revealing the mechanism of skin aging and rationally utilizing endocrine hormones to improve skin aging, which has a broad application prospect.
    Keywords:  Collagen; Melatonin; Mitophagy; Proline; Skin aging
    DOI:  https://doi.org/10.1016/j.exger.2025.112738
  5. Cells. 2025 Mar 13. pii: 431. [Epub ahead of print]14(6):
      The 20-hydroxyecdysone (20E) has been used in traditional medicine for a long time and acquired attention in the last decade as a food supplement and stimulant in physical activities. This polyhydroxylated cholesterol is found in the highest concentration in plants, and it is one of the secondary plant products that has a real hormonal influence in arthropods. Various beneficial effects have been reported in vivo and in vitro for 20E and its related compounds in mammals. Trials for the safety of clinical application showed a remarkably high tolerance in humans. This review aims to assess the latest development in the involvement of various pathways in tissues and organs and look if it is plausible to find a single primary target of this compound. The similarities with agents mimicking calorie restriction and anti-aging effects are also elucidated and discussed.
    Keywords:  20-hydroxyecdysone; 20E; beta-ecdysone; ecdysterone
    DOI:  https://doi.org/10.3390/cells14060431
  6. Sci Adv. 2025 Mar 28. 11(13): eadu1710
      Metabolic dysregulation represents one of the major driving forces in aging. Although multiple genetic and pharmacological manipulations are known to extend longevity in model organisms, aging is a complex trait, and targeting one's own genes may be insufficient to prevent age-dependent deterioration. An alternative strategy could be to use enzymes from other species to reverse age-associated metabolic changes. In this review, we discuss a set of enzymes from lower organisms that have been shown to affect various metabolic parameters linked to age-related processes. These enzymes include modulators of steady-state levels of amino acids (METase, ASNase, and ADI), NADPH/NADP+ and/or reduced form of coenzyme Q (CoQH2)/CoQ redox potentials (NDI1, AOX, LbNOX, TPNOX, EcSTH, RquA, LOXCAT, Grubraw, and ScURA), GSH (StGshF), mitochondrial membrane potential (mtON and mito-dR), or reactive oxygen species (DAAO and KillerRed-SOD1). We propose that leveraging non-mammalian enzymes represents an untapped resource that can be used to delay aging and age-related diseases.
    DOI:  https://doi.org/10.1126/sciadv.adu1710
  7. Aging Dis. 2025 Mar 15.
      The aging immune system presents profound challenges, notably through the decline of T cell function, which is critical for effective immune responses. As age-related changes lead to diminished T cell diversity and heighten immunosuppressive environments, older individuals face increased susceptibility to infections, autoimmune diseases, and reduced efficacy of immunotherapies. This review investigates the intricate mechanisms by which T cell aging drives immunosenescence, including immune suppression, immune evasion, reduced antigen reactivity, and the overexpression of immune checkpoint molecules. By delving into innovative therapeutic strategies aimed at rejuvenating T cell populations and modifying the immunological landscape, we highlight the potential for enhancing immune resilience in the elderly. Ultimately, our goal is to outline actionable pathways for restoring immune function, thereby improving health outcomes for aging individuals facing immunological decline.
    DOI:  https://doi.org/10.14336/AD.2025.0061
  8. Aging Cell. 2025 Mar 25. e70042
      Macrophages are key regulators of skeletal muscle regeneration, yet the specific macrophage subpopulations responsible for this process and their cell-cell interactions remain insufficiently understood, as does the mechanism underlying age-related impairment of skeletal muscle regeneration. We utilized single-cell RNA sequencing to identify transcriptionally distinct macrophage subpopulations within skeletal muscle from young (8-week-old) and aged (24-month-old) mice. Among them, the Mac_1 subpopulation interacted with muscle satellite cells (MuSCs) and promoted their proliferation through HGF/c-Met signaling that suppressed Cdkn1b expression. This interaction was critical for efficient muscle regeneration in vivo and in a 3D-muscle organoid model. The age-related decline in muscle regeneration was associated with reduced HGF expression in Mac_1 macrophages. Administration of exogenous HGF to aged mice and macrophage-depleted young mice partially rescued the impaired muscle regeneration. This study elucidates a mechanism of skeletal muscle regeneration that offers insight into potential strategies for preventing and treating skeletal muscle diseases, including sarcopenia.
    Keywords:  macrophage; organoid; regeneration; single‐cell RNA‐sequence; skeletal muscle stem cells
    DOI:  https://doi.org/10.1111/acel.70042
  9. Clin Cosmet Investig Dermatol. 2025 ;18 677-686
       Background: The aging of skin has important impact on various systems, and certain skin aging (SG) markers can not only help with early diagnosis, but also provide new ideas for pathophysiological research and treatment strategies.
    Objective: To identify target genes related to SG through bioinformatics technology and provide ideas for skin anti-aging.
    Methods: Differential expression genes (DEGs) related to SG were screened through transcriptome information from GEO datasets (GSE85358 and GSE670988). Based on eQTL and GWAS datasets, Mendelian Randomization (MR) analysis was applied to identify associations between gene expression and SG. Then, aging skin related important genes (AS-IGs) were obtained based on above two steps, and functional and pathway analyses were performed to explore the potential mechanisms AS-IGs in SG. Finally, the CIBERSORT evaluation was used to assess the infiltration of immune cells related to SG.
    Results: Seven AS-IGs were selected through intersection from 612 DEGs and 399 eQTL genes. Then, enrichment analysis results showed there were 60 GO terms may involved in the process of SG, like fatty-acyl-CoA metabolic process, while KEGG enrichment pathways identified mainly involved in mechanisms related to fatty acid metabolism, energy generation, and inflammation regulation. The CIBERSORT evaluation showed that NK cells resting were the main infiltrating cells.
    Conclusion: AS-IGs may play important roles in the process of SG in the body. These molecules involve multiple systems and mechanisms in the body, such as immune function, metabolic function, and neuroendocrine function.
    Keywords:  GWAS; Mendelian analysis; biomarkers; eQTL; skin aging
    DOI:  https://doi.org/10.2147/CCID.S508946
  10. Biochem Biophys Res Commun. 2025 Mar 20. pii: S0006-291X(25)00391-2. [Epub ahead of print]759 151677
      This study aims to investigate the effects of long-term aerobic exercise on liver health in aging rats. As age increases, the continuous accumulation of endogenous reactive oxygen species (ROS) damages hepatocytes, leading to liver function decline and the development of diseases such as cirrhosis and liver cancer. Using an 18-month-old rat model, we implemented an eight-month aerobic exercise regimen to systematically evaluate its hepatoprotective effects. The results showed that aerobic exercise effectively reduced oxidative stress and inflammation levels in liver tissue, decreased the expression of cell cycle regulator P53 and inflammatory regulator NF-κB protein, upregulated NRF2 protein expression, improved mitochondrial function, and inhibited the progression of ferroptosis. These beneficial effects were achieved through the upregulation of miR-21 and miR-224 expression induced by exercise. These microRNAs inhibit the translation of MAP2K3 and MAPK14, thereby suppressing the activation of the P38 MAPK pathway. We further found that inhibiting P38 MAPK can enhance cellular antioxidant and anti-inflammatory capabilities, reversing hepatocyte damage caused by hydrogen peroxide. These results demonstrate that long-term aerobic exercise can reprogram aging-related oxidative stress and metabolic pathology by regulating miRNAs and the P38 MAPK pathway, thereby helping to prevent age-related liver diseases.
    Keywords:  Aerobic exercise; Aging; Inflammation; Liver health; Oxidative stress; P38 MAPK; miRNA
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151677
  11. Biomed Pharmacother. 2025 Mar 24. pii: S0753-3322(25)00194-5. [Epub ahead of print]186 118000
       BACKGROUND AND AIM: Aging has an impact on Natural Killer (NK) cells surveillance against tumors and infections. Our study aims to assess the aging effects on metabolic and mitochondrial markers influencing NK cell activity.
    METHODS: C57BL/6 J mice aged 12, 24, 48, and 72 weeks were used. Liver injury serum and histological markers, pro-inflammatory cytokines [IL-1β, IL-2, IL-6] and chemoattractant markers [CCL2, CXCL8] were assessed. Moreover, cholesterol metabolic markers [HMG-CoA synthetase, HMG-CoA reductase, mevalonate kinase], mitochondrial biogenesis [PGC1α] and functional gene markers [TFAM, HSPA9, Seahorse, apoptosis] in liver trNK cells, were assessed by RT-PCR. Senescence [p16, p21], exhaustion [PD-1, TIGIT, LAG3], activation [CD107a, NKp46], and chemokine receptor [CCR2, CXCR1] markers were assessed in trNK cells using flow cytometry. Liver trNK cells of aged mice were treated with Rosuvastatin [10μM] for 12 h.
    RESULTS: Data showed a linear increase in liver injury markers, pro-inflammatory and chemotaxis along aging. These results were associated with reductions in liver trNK cell counts and activations with a noticeable decrease in their chemoattractant receptor expressions. TrNK cells of aged mice exhibited elevated markers of senescence and exhaustion with a gradual increase in cholesterol accumulation. Mitochondrial biogenesis and functional gene markers showed a decrease in their expressions in aged mice while ameliorated following rosuvastatin treatment. Results were correlated with a decrease in cholesterol metabolism and restoring their NK cell activity.
    CONCLUSION: Our study demonstrates age-related cholesterol accumulation in trNK cells correlated with senescence and functional impairment. Rosuvastatin is suggested to boost, rejuvenate and recover NK cell functionality.
    Keywords:  Aging; Immunosenescence; Liver fibrosis; Statins; TrNK cells
    DOI:  https://doi.org/10.1016/j.biopha.2025.118000
  12. J Ethnopharmacol. 2025 Mar 21. pii: S0378-8741(25)00352-6. [Epub ahead of print] 119668
       ETHNOPHARMACOLOGICAL RELEVANCE: The root of aging is attributed to kidney essence insufficiency and gradual loss of kidney function. The combination of Epimedii Folium and Ligustri Lucidi Fructus (ELL) is traditionally recognized to tonify kidney yin and yang and has significant efficacy in delaying aging and aging-related diseases, but little is known about the exact mechanism.
    AIM OF THE STUDY: The research focuses on the mechanism of delaying renal aging by which ELL regulates mitophagy through serine/threonine kinase AMP-activated protein kinase (AMPK) /UNC-51- like autophagy activating kinase 1 (ULK1) /B-cell lymphoma-2-like protein 13 (Bcl2L13) in vivo.
    MATERIALS AND METHODS: We employed a rat model of natural aging, using rats of different ages as dynamic controls, and a natural aging mouse model to evaluate the effects of ELL on delaying renal aging via AMPK/ULK1/Bcl2L13. The assessment included renal histopathology, oxidative stress, cell senescence, mitochondrial dynamics, mitophagy, and the AMPK/ULK1/Bcl2L13 signaling pathway. In the aging rat model, network pharmacology and proteomics were combined to dissect the renal aging process, and a Multilayer Perceptron (MLP) -artificial neural networks (ANN) model was used to evaluate the effects of ELL comprehensively. In the aging mouse model, the AMPK inhibitor dorsomorphin was applied to assess whether the AMPK signaling pathway was involved in ELL-induced mitophagy.
    RESULTS: Compared with the young rats, the kidney exhibited signs of degenerative pathologies and increased oxidative stress in 17-month-old rats. A thorough analysis identified the mitochondrial protein Bcl2L13 as a crucial biomarker associated with renal aging. The AMPK/ULK1/Bcl2L13 pathway significantly regulated mitochondrial function and mitophagy, which were potential mechanisms underlying renal aging. In contrast to aged rats, the renal pathological changes and cell senescence in rats treated with ELL were significantly mitigated, the antioxidant capacity, mitochondrial dynamics, and mitophagy were improved, and the expression of AMPK/ULK1/Bcl2L13 was upregulated. After the application of AMPK inhibitors, the effects of ELL were reversed. It appears that ELL modulates the AMPK/ULK1/Bcl2L13 signaling pathway, and upregulates mitophagy to potentially decelerate renal aging.
    CONCLUSIONS: The findings indicate that aging kidneys display mitochondrial dysfunction, disorganization of mitochondria, and a decrease in mitophagy. Concurrently, ELL significantly regulates mitochondrial dynamics and mitophagy via AMPK/ULK1/Bcl2L13. This regulation helps mitigate mitochondrial dysfunction, suggesting ELL as a promising herbal remedy for delaying renal aging and age-related kidney diseases.
    Keywords:  AMPK/ULK1/Bcl2L13 signaling pathway; Epimedii Folium/Ligustri Lucidi Fructus; Mitophagy; Renal aging
    DOI:  https://doi.org/10.1016/j.jep.2025.119668
  13. Front Bioeng Biotechnol. 2025 ;13 1554825
       Introduction: Skin aging is an inevitable physiological process driven by factors like cellular senescence, ultraviolet radiation (UV) radiation, and environmental pollutants. A key feature is the accelerated collagen degradation in the dermal extracellular matrix, leading to visible signs such as sagging, wrinkles, and hyperpigmentation. Traditional fillers, such as hyaluronic acid and collagen-based fillers, offer only temporary volume enhancement without stimulating collagen regeneration. Studies have shown that electrical signals generated by piezoelectric materials can promote tissue regeneration.
    Methods: This study explored the potential of piezoelectric PHBHHx microspheres as an innovative skin filler for enhancing collagen regeneration and improving maxillofacial aesthetics, with the aid of low-intensity pulsed ultrasound (LIPUS) stimulation. A comprehensive characterizations of the piezoelectric PHBHHx microspheres were conducted, and their potential to stimulate collagen regeneration was assessed using a subcutaneous injection model in New Zealand white rabbits.
    Results: The results indicated that PHBHHx microspheres exhibited stable degradation properties, great piezoelectric properties and excellent biocompatibility. Moreover, when stimulated by LIPUS, the collagen-regenerating effect of PHBHHx microspheres was further enhanced, histological analysis revealed a denser and more organized collagen structures in LIPUS-stimulated PHBHHx group.
    Discussion: These findings highlight the potential of PHBHHx microspheres as an advanced biomaterial for applications in aesthetic medicine, particularly in promoting collagen regeneration and enhancing skin rejuvenation.
    Keywords:  LIPUS; PHBHHx; collagen regeneration; piezoelectric; skin rejuvenation
    DOI:  https://doi.org/10.3389/fbioe.2025.1554825
  14. J Sci Food Agric. 2025 Mar 24.
       BACKGROUND: Tenebrio molitor, commonly known as the mealworm, is globally accepted and recognized as an edible insect with a high nutritional profile and potential health benefits. Mealworms are sustainable protein sources for addressing future food security. This study aimed to investigate the anti-aging properties of mealworm aqueous extracts and protein concentrate using Caenorhabditis elegans as a model organism.
    RESULTS: C. elegans treated with mealworm protein concentrate and aqueous extracts (60 μg mL-1) exhibited a significant enhancement of lifespan by 10-26.4% (P ≤ 0.05) under normal conditions. Stress tolerance survival of the treated nematodes was improved by 83-91% (P ≤ 0.05) under thermal stress, and an extended lifespan of 1-2 days was observed under UV exposure. Additionally, reactive oxygen species were significantly reduced, with a fold change of 0.54-0.7 (P ≤ 0.05) compared to control. Structural improvements in nematodes treated with mealworm-derived bioactives included enhanced pharyngeal integrity, reduced lipofuscin content, lower lipid accumulation and prevention of intestinal permeability. These changes highlight the role of mealworm protein concentrate and extracts in maintaining cellular health, improving metabolic functions and mitigating aging-related deterioration. These effects were supported by increased antioxidant enzyme activities (superoxide dismutase and catalase) and the activation of stress response pathways mediated by hsf-1 and skn-1.
    CONCLUSION: The study demonstrated that mealworm aqueous extracts and protein concentrate possess significant anti-aging properties and improve stress resilience in C. elegans. These findings highlight the potential of mealworm-derived products in mitigating age-related health issues, with promising applications in cosmeceuticals and nutraceuticals. © 2025 Society of Chemical Industry.
    Keywords:  C. elegans; antioxidant; life span; mealworm aqueous extracts; mealworm protein concentrates
    DOI:  https://doi.org/10.1002/jsfa.14229
  15. Biology (Basel). 2025 Mar 09. pii: 279. [Epub ahead of print]14(3):
      Aging is a time-dependent process of functional decline influenced by genetic and environmental factors. Age-related mitochondrial changes remain incompletely understood. Here, we found that compared to the wild type, the mitochondria of long-lived daf-2 C. elegans maintain youthful morphology and function. Through quantitative proteomic analysis on isolated mitochondria, we identified 257 differentially expressed candidates. Analysis of these changed mitochondrial proteins reveals a significant upregulation of five key mitochondrial metabolic pathways in daf-2 mutants, including branched-chain amino acids (BCAA), reactive oxygen species (ROS), propionate, β-alanine, and fatty acids (FA), all of which are related to daf-2-mediated longevity. In addition, mitochondrial ribosome protein abundance slightly decreased in daf-2 mutants. A mild reduction in mitochondrial elongation factor G (gfm-1) by RNAi extends the lifespan of wild type while decreasing lipid metabolic process and cytoplasmic fatty acid metabolism, suggesting that proper inhibition of mitochondrial translation activity might be important for lifespan extension. Overall, our findings indicate that mitochondrial metabolic modulation contributes to the longevity of daf-2 mutants and further highlights the crucial role of mitochondria in aging.
    Keywords:  DAF-2; aging; metabolism; mitochondria; quantitative proteomics
    DOI:  https://doi.org/10.3390/biology14030279
  16. Pharmaceuticals (Basel). 2025 Feb 27. pii: 344. [Epub ahead of print]18(3):
      Age-related oxidative stress is a critical factor in vascular dysfunction, contributing to hypertension and atherosclerosis. Smooth muscle cells and endothelial cells are particularly susceptible to oxidative damage, which exacerbates vascular aging through cellular senescence, chronic inflammation, and arterial stiffness. Gasotransmitters-hydrogen sulfide (H2S), nitric oxide (NO), and carbon monoxide (CO)-are emerging as promising therapeutic agents for counteracting these processes. This review synthesizes findings from recent studies focusing on the mechanisms by which H2S, NO, and CO influence vascular smooth muscle and endothelial cell function. Therapeutic strategies involving exogenous gasotransmitter delivery systems and combination therapies were analyzed. H2S enhances mitochondrial bioenergetics, scavenges ROS, and activates antioxidant pathways. NO improves endothelial function, promotes vasodilation, and inhibits platelet aggregation. CO exhibits cytoprotective and anti-inflammatory effects by modulating heme oxygenase activity and ROS production. In preclinical studies, gasotransmitter-releasing molecules (e.g., NaHS, SNAP, CORMs) and targeted delivery systems show significant promise. Synergistic effects with lifestyle modifications and antioxidant therapies further enhance their therapeutic potential. In conclusion, gasotransmitters hold significant promise as therapeutic agents to combat age-related oxidative stress in vascular cells. Their multifaceted mechanisms and innovative delivery approaches make them potential candidates for treating vascular dysfunction and promoting healthy vascular aging. Further research is needed to translate these findings into clinical applications.
    Keywords:  carbon monoxide; endothelial cells; gasotransmitters; hydrogen sulfide; nitric oxide; oxidative stress; smooth muscle cells; vascular aging
    DOI:  https://doi.org/10.3390/ph18030344
  17. Front Pharmacol. 2025 ;16 1557703
       Introduction: Sarcopenia is a condition characterized by the loss of muscle fibers and excessive deposition of extracellular matrix proteins. The interplay between muscle atrophy and fibrosis is a central feature of sarcopenia. While the mechanisms underlying skeletal muscle aging and fibrosis remain incompletely understood, cellular senescence has emerged as a key contributor. This study investigates the role of D-galactose (D-gal) in inducing fibroblasts senescence and skeletal muscle fibrosis, and aims to find the key regulator of the process to serve as a therapeutical target.
    Methods: To discover the role of D-gal in inducing cellular senescence and fibrosis, the senescence markers and the expression of fibrosis-related proteins were assessed after introducing D-gal among fibroblasts, and muscle strength and mass. The severity of muscle atrophy and fibrosis were also verified by using H&E staining and Masson trichrome staining after D-gal treatment via subcutaneous injection among mice. Subsequently, mRNA sequencing (RNA-seq) was performed and the differential expressed genes were identified between under D-gal or control treatment, to discover the key regulator of D-GAL-driven fibroblasts senescence and fibrosis. The role of the key regulator IGFBP5 were then validated in D-GAL treated IGFBP5-knockdown fibroblasts in vitro by analyzing the level of senescence and fibrosis-related markers. And the results were further confirmed in vivo in IGFBP5-knockdown SAMP8 mice with histological examinations.
    Results: D-gal treatment effectively induced cellular senescence and fibrosis in fibroblasts, as well as skeletal muscle atrophy, fibrosis and loss in muscle mass and function in mice. IGFBP5 was identified as a key regulator of D-GAL induced senescence and fibrosis among fibroblasts using RNA-seq. And further validation tests showed that IGFBP5-knockdown could alleviate D-GAL-induced fibroblast cellular senescence and fibrosis, as well as the severity of muscle atrophy and fibrosis in SAMP8 mice.
    Discussion: IGFBP5 emerging as a key regulator of D-GAL-induced fibroblast cellular senescence and fibrosis. The findings provide new insights into the molecular mechanisms underlying age-related skeletal muscle fibrosis and highlight IGFBP5 as a potential therapeutic target. Further research is needed to validate these findings and explore related clinical applications.
    Keywords:  fibrosis; sarcopenia; skeletal muscle aging; skeletal muscle fibroblasts; skeletal muscle fibrosis
    DOI:  https://doi.org/10.3389/fphar.2025.1557703
  18. Adv Biol (Weinh). 2025 Mar 24. e2400597
      Mitochondrial dysfunction is an irrefutable hallmark of cellular senescence and aging. The dysfunction is marked by increased mitochondrial volume and reduced function, typified by low Adenosine Triphosphate (ATP) production and higher Reactive Oxygen Species (ROS) generation. Over the years, this dysfunction has been linked to Electron Transport Chain (ETC) malfunction and low NAD levels, augmented by poor mitophagy. However, the genetic regulation of mitochondrial dysfunction is still not clear. Here, using several senescence models, the first report on the role of the downregulation of a mitochondrial protein, Translocase of Inner Mitochondrial Membrane 50 (TIMM50), in senescence is presented. The downregulation of TIMM50 is also sufficient for triggering senescence through impaired mitochondrial function, characterized using a variety of mitochondrial function assessment assays. Reduced levels of TIMM50 initiated all the hallmarks of senescence, and overexpression significantly slowed senescence onset in response to an external trigger. The pathway analysis revealed that TIMM50 loss is mediated by the sirtuin1-dependent downregulation of CCAAT enhancer binding protein alpha (CEBPα), a transcription activator for TIMM50 expression. To establish the translational value of the observation, screening several potential anti-aging compounds revealed TIMM50 stabilizing and senescence-delaying effects only for verapamil and mitochondrial ROS quencher, Mito (2-(2,2,6,6-Tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl)triphenylphosphonium chloride (MitoTEMPO), both known anti-aging entities. Overall, TIMM50 is identified as the key mitochondrial protein whose downregulation is a critical step in initiating cellular senescence.
    Keywords:  TIMM50; aging; cellular senescence; mitochondria; sirtuin
    DOI:  https://doi.org/10.1002/adbi.202400597
  19. PLoS One. 2025 ;20(3): e0319770
      To investigate the effect of pyrroloquinoline quinone (PQQ) on skin aging in the Bmi-1 KO mice and its underlying mechanisms, we administered a normal diet to both Wild type mice (WT) and Bmi-1 KO mice, while supplementing the diet of Bmi-1 KO mice with PQQ (PQQ+Bmi-1 KO). Subsequently, we compared the thickness of the skin epidermis, dermis, pilosebaceous unit and collagen ratio using HE staining and Masson's trichrome. Additionally, immunohistochemical staining, Western blotting and electron microscopy were applied across all three groups. The results revealed that Bmi-1 KO mice exhibited premature aging phenotypes compared to the WT group; however, PQQ administration effectively delayed premature aging in Bmi-1 KO mice. Furthermore, reduced epidermal thickness, dermal thickness, pilosebaceous units count as well as collagen ratio were observed in Bmi-1 KO mice. Moreover, the PCNA positive cell percentage also decreased in Bmi-1 KO mice. Conversely, treatment with PQQ significantly increased epidermal thickness, dermal thickness, pilosebaceous unit count, collagen ratio and PCNA positive cell percentage when compared to Bmi-1 KO mice. In order to further investigate the anti-aging mechanism of PQQ, experiments have revealed that PQQ effectively suppressed the expression of cell cycle proteins p16, p19, and p53 in Bmi-1 KO mice. In addition, autophagy-related experiments demonstrated that compared to the WT group, Bmi-1 KO mice exhibited an increased number of autophagosomes along with decreased expression of Beclin-1 and LC3Ⅱ/LC3Ⅰratio, and increased expression of p62. However, supplementation with PQQ resulted in a reduction in the number of autophagosomes while increasing the expression of Beclin-1 and LC3Ⅱ/LC3Ⅰratio and decreasing the expression of p62. This study provides evidence that downregulation of Bmi-1 promotes skin aging, whereas PQQ delays skin aging in Bmi-1 KO mice by promoting cell proliferation, inhibiting the expression of p16, p19 and p53 and enhancing autophagy levels.
    DOI:  https://doi.org/10.1371/journal.pone.0319770
  20. Cell Prolif. 2025 Mar 24. e70026
      Ageing is often accompanied by cognitive decline and an increased risk of dementia. Exercise is a powerful tool for slowing brain ageing and enhancing cognitive function, as well as alleviating depression, improving sleep, and promoting overall well-being. The connection between exercise and healthy brain ageing is particularly intriguing, with exercise-induced pathways playing key roles. This review explores the link between exercise and brain health, focusing on how skeletal muscle influences the brain through muscle-brain crosstalk. We examine the interaction between the brain with well-known myokines, including brain-derived neurotrophic factor, macrophage colony-stimulating factor, vascular endothelial growth factor and cathepsin B. Neuroinflammation accumulates in the ageing brain and leads to cognitive decline, impaired motor skills and increased susceptibility to neurodegenerative diseases. Finally, we examine the evidence on the effects of exercise on neuronal myelination in the central nervous system, a crucial factor in maintaining brain health throughout the lifespan.
    Keywords:  CNS myelination; brain; brain ageing; exercise; healthy ageing; myokines and brain health
    DOI:  https://doi.org/10.1111/cpr.70026
  21. Front Biosci (Landmark Ed). 2025 Mar 19. 30(3): 25728
      The relationship between polyphenols and autophagy, particularly in the context of aging, presents a promising avenue for therapeutic interventions in age-related diseases. A decline in autophagy is associated with aging-related affections, and an increasing number of studies suggest that this enhancement is linked to cellular resilience and longevity. This review delves into the multifaceted roles of autophagy in cellular homeostasis and the potential of polyphenols to modulate autophagic pathways. We revised the most updated literature regarding the modulatory effects of polyphenols on autophagy in cardiovascular, liver, and kidney diseases, highlighting their therapeutic potential. We highlight the role of polyphenols as modulators of autophagy to combat age-related diseases, thus contributing to improving the quality of life in aging populations. A better understanding of the interplay of autophagy between autophagy and polyphenols will help pave the way for future research and clinical applications in the field of longevity medicine.
    Keywords:  aging; autophagy; polyphenols
    DOI:  https://doi.org/10.31083/FBL25728
  22. Int J Biol Macromol. 2025 Mar 20. pii: S0141-8130(25)02944-7. [Epub ahead of print]308(Pt 1): 142392
      Oxidative stress within the body is associated with aging, playing a crucial role in its progression. Polysaccharides from lactic acid bacteria are well recognized for their antioxidant effects, potentially improving the aging process. This study investigated the characterization and antioxidant activities of extracellular polysaccharides (EPS-1: 59,978 Da, 40.9 % mannose, 4.5 % ribose, 5.8 % glucuronic acid, 44.1 % glucose, 2.9 % galactose; EPS-2: 25,686 Da, 22.9 % mannose, 5.4 % ribose, 5.5 % glucuronic acid, 59.6 % glucose, 5.4 % galactose) produced by Lactiplantibacillus plantarum R6-1. The results showed that EPS could increase the survival rates of Caco-2 cells exposed to hydrogen peroxide and mitigate the D-galactose (D-Gal)-induced oxidative stress in mice. Administration of EPS activated the hepatic nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in mice. Subsequently, this pathway activated various oxidation-related enzymes such as superoxide dismutase, catalase, and glutathione peroxidase. Meanwhile, EPS regulated mouse intestinal microbiota by increasing the relative abundance of beneficial bacteria secreting anti-inflammatory factors, such as Norank_f_Muribaculaceae and Dubosiella, and restoring the imbalance of Firmicutes to Bacteroidetes caused by oxidative stress. This study shows that L. plantarum R6-1's EPS exhibited the ability to concurrently influence both the liver and intestinal microbiota of mice, thereby achieving an anti-oxidative effect through their interconnected interactions.
    Keywords:  Anti-aging; Extracellular polysaccharide; Intestinal microbiota-hepatic axis; Lactiplantibacillus plantarum R6-1; Nrf2 pathway; Oxidative stress
    DOI:  https://doi.org/10.1016/j.ijbiomac.2025.142392
  23. Food Sci Biotechnol. 2025 Apr;34(8): 1713-1723
      The retinal pigmented epithelium (RPE) is constantly exposed to visible light, including blue light (BL) that creates reactive oxygen species (ROS), which are harmful to DNA and induce cellular senescence. Carotenoids are recognized for their antioxidant properties, but their protective effect on DNA repair and cellular senescence under BL induced oxidative stress has not been evaluated. After BL irradiation, the positive senescence-associated-β-galactosidase (SA-β-gal) staining, and gene expression of p16 INK4a and p21 Waf/Cip1 were upregulated in ARPE-19 cells. Pretreatment with carotenoids reduced ROS, p-H2A.X nuclear foci, and SA-β-gal positive cells induced by BL irradiation. Furthermore, pretreatment with carotenoids reduced the secretion of IL-6 and VEGF triggered by BL. Since increased senescent cells and secretion of IL-6 and VEGF are involved in age-related macular degeneration pathogenesis, our results support that carotenoid supplementation has a potential role in protecting the eyes from the deleterious effects of excessive BL exposure.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-024-01757-z.
    Keywords:  ARPE-19; Blue-light; Cellular senescence; DNA damage; Oxidative stress
    DOI:  https://doi.org/10.1007/s10068-024-01757-z
  24. Pharmaceuticals (Basel). 2025 Mar 13. pii: 403. [Epub ahead of print]18(3):
      Background: Carotenoids are bioactive tetraterpenoid C40 pigments that are actively synthesized by plants, bacteria, and fungi. Compounds such as α-carotene, β-carotene, lycopene, lutein, astaxanthin, β-cryptoxanthin, fucoxanthin, and zeaxanthin have attracted increasing attention for their antiaging properties. They exhibit antioxidant, neuroprotective, and anti-inflammatory properties, contributing to the prevention and treatment of age-related diseases. Objectives: The aim of this study was to comprehensively analyze the pharmacological potential and biological mechanisms of carotenoids associated with age-related disorders and to evaluate their application in nutraceuticals, pharmaceuticals, and cosmeceuticals. Methods: A systematic review of studies published over the past two decades was conducted using the databases PubMed, Scopus, and Web of Science. The selection criteria included clinical, in silico, in vivo, and in vitro studies investigating the pharmacological and therapeutic effects of carotenoids. Results: Carotenoids demonstrate a variety of health benefits, including the prevention of age-related macular degeneration, cancer, cognitive decline, metabolic disorders, and skin aging. Their role in nutraceuticals is well supported by their ability to modulate oxidative stress and inflammatory pathways. In pharmaceuticals, carotenoids show promising results in formulations targeting neurodegenerative diseases and metabolic disorders. In cosmeceuticals, they improve skin health by protecting it against UV radiation and oxidative damage. However, bioavailability, optimal dosages, toxicity, and interactions with other bioactive compounds remain critical factors to maximize therapeutic efficacy and still require careful evaluation by scientists. Conclusions: Carotenoids are promising bioactive compounds for antiaging interventions with potential applications in a variety of fields. Further research is needed to optimize their formulas, improve bioavailability, and confirm their long-term safety and effectiveness, especially in the aging population.
    Keywords:  age-related disorders; antiaging properties; astaxanthin; fucoxanthin; lutein; lycopene; pharmacological effects; possible toxic effects; zeaxanthin; α-carotene; β-carotene; β-cryptoxanthin
    DOI:  https://doi.org/10.3390/ph18030403
  25. Nature. 2025 Mar;639(8056): 841
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-00770-4
  26. Ageing Res Rev. 2025 Mar 20. pii: S1568-1637(25)00079-0. [Epub ahead of print]108 102733
      Following the demographic shift towards an ageing population over the past century, particularly in developed countries, the concept of healthspan has gained increasing acceptance as a key framework for understanding the drivers of healthy ageing. Accordingly, long-lived individuals, such as nonagenarians and centenarians, who remain free from chronic diseases, provide a valuable model to investigate the complex interplay of biological, genetic, and environmental factors that contribute to exceptional longevity. Although there are other longevity hotspots worldwide, five regions, known as Blue Zones, are widely recognized for their exceptionally long-lived populations. Among the various determinants of healthy ageing, the eating patterns of long-lived individuals in Blue Zones include a variety of polyphenol-rich foods, which may contribute to their healthy phenotype. A significant body of evidence suggests that polyphenols, a large family of compounds ubiquitously found in plant-based foods, may exhibit geroprotective activity by influencing underlying biological mechanisms of ageing and promoting optimal longevity. While identifying several knowledge gaps that future investigations should address, the goal of this review is to provide an overview of how specific polyphenols found in foods commonly consumed by long-lived individuals residing in the Blue Zones may mitigate the risk of age-related diseases. Additionally, we discuss how these compounds, by acting on evolutionarily conserved mechanisms associated with ageing, have the potential to modulate the intricate network of the hallmarks of ageing.
    Keywords:  Ageing; Blue Zones, Centenarians; Diet, Geroprotection; Polyphenols
    DOI:  https://doi.org/10.1016/j.arr.2025.102733
  27. J Med Food. 2025 Mar 24.
      Skin aging, accelerated by oxidative stress from environmental factors, results in the breakdown of collagen and elastin, causing visible signs like wrinkles and inflammation. Natural antioxidants such as nicotinamide mononucleotide (NMN), decursin, and l-cysteine have shown potential in combating oxidative damage and inflammation. This study explored the effects of a formulated mixture of these compounds on skin aging and atopic dermatitis (AD) through a combination of in vitro, in vivo, and in silico methods. Using human keratinocyte cells, we assessed cytotoxicity via a cell viability assay, confirming NMN and l-cysteine were nontoxic up to 100 µM, while decursin exhibited toxicity above 10 µM. The intracellular oxidative stress measurement demonstrated that mixtures A and B, composed of the same concentrations of decursin and l-cysteine but differing in NMN levels (low in mixture A and moderate in mixture B), significantly reduced oxidative stress levels induced by 2,2'-azobis(2-amidinopropane) dihydrochloride, whereas mixture C, which contained the highest NMN concentration, was ineffective. Mixture B further reduced senescence-associated heterochromatin foci formation under oxidative stress, while mixture C caused cell structure disruptions. In the dinitrochlorobenzene-induced AD model in BALB/c mice, both, mixture-L and mixture-H treatments reduced epidermal thickness, scratching behavior, and transepidermal water loss, with mixture-L also lowering dermal thickness and mast cell infiltration. Gene expression analysis confirmed that mixture B decreased proinflammatory cytokines like TNF-α and IL-6, while network pharmacology predicted key antioxidant pathways, validated through restored NOS2 gene expression. Overall, the findings highlight the potential of these compound mixtures to mitigate oxidative stress and inflammation, offering a promising approach for skin aging and dermatitis management, though further validation is needed to optimize efficacy and safety.
    Keywords:  NMN; atopic dermatitis; decursin; inflammation; l-cysteine; nicotinamide mononucleotide; skin aging
    DOI:  https://doi.org/10.1089/jmf.2024.k.0282
  28. Biochem Biophys Res Commun. 2025 Apr 12. pii: S0006-291X(25)00353-5. [Epub ahead of print]758 151639
      Genomic stability, encompassing DNA damage and repair mechanisms, plays a pivotal role in the onset of diseases and the aging process. The stability of DNA is intricately linked to the chemical and mechanical forces exerted on chromatin, particularly within lamina-associated domains (LADs). Mechanical stress can induce DNA damage through the deformation and rupture of the nuclear envelope, leading to DNA bending and cleavage. However, DNA can evade such mechanical stress-induced damage by relocating away from the nuclear membrane, a process facilitated by the depletion of H3K9me3-marked heterochromatin and its cleavage from the lamina. When DNA double-stranded breaks occur, they prompt the rapid recruitment of Lamin B1 and the deposition of H3K9me3. Despite these insights, the precise mechanisms underlying DNA damage and repair under mechanical stress remain unclear. In this review, we explore the interplay between mechanical forces and the nuclear envelope in the context of DNA damage, elucidate the molecular pathways through which DNA escapes force-induced damage, and discuss the corresponding repair strategies involving the nuclear cytoskeleton. By summarizing the mechanisms of force-induced DNA damage and repair, we aim to underscore the potential for developing targeted therapeutic strategies to bolster genomic stability and alleviate the impacts of aging and disease.
    Keywords:  DNA double-strand breaks; DNA repair; Lamin B1; Lamina-associated domain; Mechanical stress
    DOI:  https://doi.org/10.1016/j.bbrc.2025.151639
  29. Int J Mol Sci. 2025 Mar 15. pii: 2664. [Epub ahead of print]26(6):
      β-hydroxy-β-methylbutyrate (HMB) has been shown to enhance muscle function and strength in older humans and rodents after periods of consumption extending for several weeks. We investigated the feasibility of utilizing Drosophila as a model organism to study the biological effects of HMB on aging muscle when consumed throughout adult life. Using flight ability as an index of flight muscle function, we found that HMB attenuates the age-dependent decline in flight ability. Male and female flies fed a diet supplemented with 10 mg/mL HMB had significantly higher flight scores from median age until the onset of flight senescence than control flies fed a standard diet. HMB supplementation also resulted in improved flight scores in males before median age and delayed the onset of flight senescence in females. Notably, the consumption of HMB throughout adult life increased the rate of survival and extended lifespan. The effect on lifespan did not result from changes in food consumption or body weight. Old flies on the HMB-supplemented diet retained a higher proportion of flight muscle mitochondria whose morphology resembled that of young flies than the control diet group. Together, these results suggest that HMB attenuates the age-dependent decline in flight ability and prolongs lifespan by enhancing muscle health.
    Keywords:  Drosophila; HMB; aging; flight muscle; lifespan; mitochondria
    DOI:  https://doi.org/10.3390/ijms26062664
  30. NPJ Aging. 2025 Mar 26. 11(1): 21
      Samul-tang (SM) is a traditional prescription widely used in clinical practice for the management of gynecological diseases, especially for menstrual regulation and infertility treatment. We previously reported its efficacy in increasing mature oocyte production and improving ovarian reserves, potentially regulated by rat sarcoma virus (Ras) signaling in the ovaries of aged mice. Although the main ingredients of SM are known, the bioactive compounds responsible for protecting ovarian function during aging remain unidentified. This study aimed to identify the active compounds that significantly contribute to the therapeutic potential of SM against age-related decline in ovarian function. The combination of butylphthalide and oleanolic acid improved mature oocyte production similar to that in SM-administered aged mice. Subsequently, we identified butylphthalide as an active compound that mimicked SM's effect on enhancing ovarian reserve. This study introduces a novel strategy for identifying active compounds in multi-component herbal medicines by evaluating compound combinations in an in vivo model, offering promising therapeutic avenues for age-related female infertility through targeted gene expression modulation.
    DOI:  https://doi.org/10.1038/s41514-025-00214-3
  31. DNA Repair (Amst). 2025 Mar 16. pii: S1568-7864(25)00023-0. [Epub ahead of print]149 103827
      Oxidative DNA damage, resulting from endogenous cellular processes and external sources plays a significant role in mutagenesis, cancer progression, and the pathogenesis of neurological disorders. Base Excision Repair (BER) is involved in the repair of base modifications such as oxidations or alkylations as well as single strand breaks. The DNA glycosylase OGG1, initiates the BER pathway by the recognition and excision of 8oxoG, the most common oxidative DNA lesion, in both nuclear and mitochondrial DNA. Beyond DNA repair, OGG1 modulates transcription, particularly pro-inflammatory genes, linking oxidative DNA damage to broader biological processes like inflammation and aging. In cancer therapy, BER inhibition has emerged as a promising strategy to enhance treatment efficacy. Targeting OGG1 sensitizes cells to chemotherapies, radiotherapies, and PARP inhibitors, presenting opportunities to overcome therapy resistance. Additionally, OGG1 activators hold potential in mitigating oxidative damage associated with aging and neurological disorders. This review presents the development of several inhibitors and activators of OGG1 and how they have contributed to advance our knowledge in the fundamental functions of OGG1. We also discuss the new opportunities they provide for clinical applications in treating cancer, inflammation and neurological disorders. Finally, we also highlight the challenges in targeting OGG1, particularly regarding the off-target effects recently reported for some inhibitors and how we can overcome these limitations.
    Keywords:  Base excision repair; Cancer; Inflammation; OGG1 modulators; Oxidative DNA damage; Small molecules; Transcriptional regulation
    DOI:  https://doi.org/10.1016/j.dnarep.2025.103827
  32. Ageing Res Rev. 2025 Mar 21. pii: S1568-1637(25)00083-2. [Epub ahead of print] 102737
      Partial or transient cellular reprogramming is defined by the limited induction of pluripotency factors without full dedifferentiation of cells to a pluripotent state. Comparing in vitro and in vivo mouse studies, and in vitro studies in humans, supported by visualizations of data interconnections, we show consistent patterns in how such reprogramming modulates key biological processes. Generally, partial reprogramming drives dynamic chromatin remodelling, involving histone modifications that regulate accessibility and facilitate pluripotency gene activation while silencing somatic identity. These changes are accompanied by modifications in stress response programs, such as inflammation, autophagy, and cellular senescence, as well as improved mitochondrial activity and dysregulation of extracellular matrix pathways. We also underscore the challenges in evaluating complex processes like aging and cellular senescence, given the variability in biomarkers used across studies. Overall, we highlight biological processes consistently influenced by reprogramming while noting that some effects are context-dependent, varying according to cell type, species, sex, recovery time, and the reprogramming method employed. These insights inform future research and potential therapeutic applications in aging and regenerative medicine.
    Keywords:  Aging; Epigenetic clocks; Partial Reprogramming; Rejuvenation
    DOI:  https://doi.org/10.1016/j.arr.2025.102737
  33. Eur J Ageing. 2025 Mar 24. 22(1): 13
      Healthy aging requires acquiring new functional skills for adaptation in a dynamic environment. Cognitive interventions with older adults have largely focused on improving broad cognitive abilities, aiming for transfer to functional effects. By contrast, interventions focusing directly on acquiring new functional skills can address current real-world issues, including the need for reskilling and reducing the digital divide, especially for underserved communities. In doing so, we may better understand how aspects of age-related learning and cognitive and functional decline may be due to suboptimal learning circumstances rather than senescence. In this opinion paper, we highlight key aspects for designing long-lasting, real-world interventions to improve functional skills, and potentially transfer to cognitive effects, for older adults. This approach could help build more inclusive theories of cognitive aging, while progressing the field toward developing more effective and useful interventions.
    Keywords:  Cognitive aging; Cognitive interventions; Functional decline; Real-world function
    DOI:  https://doi.org/10.1007/s10433-025-00852-2
  34. Br J Nutr. 2025 Mar 27. 1-23
      The sulfur microbial diet (SMD), a dietary pattern associated with 43 sulfur-metabolizing bacteria, may influence gut microbiota composition and contribute to aging process through gut-produced hydrogen sulfide (H2S). We aimed to explore the association between SMD and biological age acceleration, using the cross-sectional study included 71,579 individuals from the UK Biobank. The SMD score was calculated by multiplying β-coefficients by corresponding serving sizes and summing them, based on dietary data collected using the Oxford WebQ, a 24-hour dietary assessment tool. Biological age (BA) was assessed using Klemerae-Doubal (KDM) and PhenoAge methods. The difference between BA and chronological age refers to the age acceleration (AgeAccel), termed "KDMAccel" and "PhenoAgeAccel". Generalized linear regression was performed. Mediation analyses were used to investigate underlying mediators including body mass index (BMI) and serum aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio. Following adjustment for multiple variables, a positive association was observed between consuming a dietary pattern with a higher SMD score and both KDMAccel (βQ4vsQ1 = 0.35, 95%CI = 0.27 to 0.44, P<0.001) and PhenoAgeAccel (βQ4vsQ1 = 0.32, 95%CI = 0.23 to 0.41, P<0.001). Each 1-standard deviation increase in SMD score was positively associated with the acceleration of biological age by 7.90% for KDMAccel (P<0.001) and 7.80% for PhenoAgeAccel (P<0.001). BMI and AST/ALT mediated the association. The stratified analysis revealed stronger accelerated aging impacts in males and smokers. Our study indicated a higher SMD score is associated with elevated markers of biological aging, supporting the potential utility of gut microbiota-targeted dietary interventions in attenuating the aging process.
    Keywords:  Klemerae Doubal method; PhenoAge; Sulfur microbial diet; biological age
    DOI:  https://doi.org/10.1017/S0007114525000534
  35. Int J Mol Sci. 2025 Mar 14. pii: 2626. [Epub ahead of print]26(6):
      Aucubin (AU) is one of the main components of the traditional Chinese medicine Eucommia ulmoides Oliv (EU). This study investigated the effects of AU on aging-related skeletal muscle atrophy in vitro and in vivo. The results of network pharmacology revealed the potential therapeutic effects of AU on muscle atrophy. In vitro, AU effectively attenuated D-gal-induced cellular damage, reduced the number of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, down-regulated the expression levels of muscle atrophy-related proteins Atrogin-1 and MuRF1, and improved myotube differentiation, thereby mitigating myotube atrophy. Notably, AU was found to attenuate oxidative stress and apoptosis in skeletal muscle cells by reducing ROS production, regulating Cleaved caspase3 and BAX/Bcl-2 expression in apoptotic pathways, and enhancing Sirt1 and PGC-1α signaling pathways. In vivo studies demonstrated that AU treatment extended the average lifespan of Caenorhabditis elegans (C. elegans), increased locomotor activity, improved body wall muscle mitochondrial content, and alleviated oxidative damage in C. elegans. These findings suggested that AU can ameliorate aging-related muscle atrophy and show significant potential in preventing and treating muscle atrophy.
    Keywords:  Aucubin; Sirt1/PGC-1α; apoptosis; muscle atrophy; oxidative stress
    DOI:  https://doi.org/10.3390/ijms26062626
  36. Nat Med. 2025 Mar 24.
      As the global population ages, it is critical to identify diets that, beyond preventing noncommunicable diseases, optimally promote healthy aging. Here, using longitudinal questionnaire data from the Nurses' Health Study (1986-2016) and the Health Professionals Follow-Up Study (1986-2016), we examined the association of long-term adherence to eight dietary patterns and ultraprocessed food consumption with healthy aging, as assessed according to measures of cognitive, physical and mental health, as well as living to 70 years of age free of chronic diseases. After up to 30 years of follow-up, 9,771 (9.3%) of 105,015 participants (66% women, mean age = 53 years (s.d. = 8)) achieved healthy aging. For each dietary pattern, higher adherence was associated with greater odds of healthy aging and its domains. The odds ratios for the highest quintile versus the lowest ranged from 1.45 (95% confidence interval (CI) = 1.35-1.57; healthful plant-based diet) to 1.86 (95% CI = 1.71-2.01; Alternative Healthy Eating Index). When the age threshold for healthy aging was shifted to 75 years, the Alternative Healthy Eating Index diet showed the strongest association with healthy aging, with an odds ratio of 2.24 (95% CI = 2.01-2.50). Higher intakes of fruits, vegetables, whole grains, unsaturated fats, nuts, legumes and low-fat dairy products were linked to greater odds of healthy aging, whereas higher intakes of trans fats, sodium, sugary beverages and red or processed meats (or both) were inversely associated. Our findings suggest that dietary patterns rich in plant-based foods, with moderate inclusion of healthy animal-based foods, may enhance overall healthy aging, guiding future dietary guidelines.
    DOI:  https://doi.org/10.1038/s41591-025-03570-5
  37. Front Bioeng Biotechnol. 2025 ;13 1564964
      Evidence has accumulated that adult tissues contain a population of early development stem cells capable of differentiating across germ layers into various types of cells. Our group purified these rare cells, naming them very small embryonic-like stem cells (VSELs). With their broad differentiation potential, VSELs have emerged as a new candidate population for clinical applications. This advancement is now possible due to our recent development of a model for ex vivo expansion of these rare cells. Importantly, no evidence suggests that VSELs, isolated from adult tissues, can form teratomas. In this review paper, we update current research on these cells reported in our laboratory as well as in those of several independent investigators.
    Keywords:  embryonic stem cells; induced pluripotent stem cells; pluripotent stem cells; tissue organ regeneration; very small embryonic-like stem cells (VSELs)
    DOI:  https://doi.org/10.3389/fbioe.2025.1564964
  38. ACS Chem Neurosci. 2025 Mar 26.
      Nuclear factor erythroid 2 related factor 2 (Nrf2) is closely associated with neurodegenerative diseases, and the Nrf2-mediated activation of antioxidant response elements (AREs) brings about validated strategies for treating neurodegenerative diseases. Here, we discovered that troglitazone, a clinical medication for diabetes mellitus, could serve as a Nrf2 activator to rescue neuronal damages both in vitro and in vivo. The mechanism of troglitazone action involves binding with kelch-like ECH-associated protein 1 (Keap1) and the activation of Nrf2. This process leads to the migration of Nrf2 to the cell nucleus and transactivates the AREs. Troglitazone exhibits significant alleviation of oxidative stress in PC12 cells induced by hydrogen peroxide or 6-hydroxydopamine (6-OHDA). In vivo studies indicate that troglitazone could rescue the motor activity and neurodevelopmental deficiency in zebrafish induced by 6-OHDA. Additionally, mass spectrometry imaging demonstrates that troglitazone could cross the zebrafish blood-brain barrier, supporting the application of troglitazone in treating neurodegenerative diseases. Overall, this work reveals that the novel Nrf2 activator troglitazone has potential therapeutic value for neurodegeneration and provides a foundation for its repurposing.
    Keywords:  6-hydroxydopamine; Nrf2; Parkinson’s disease; neuroprotection; troglitazone
    DOI:  https://doi.org/10.1021/acschemneuro.5c00163
  39. Dent J (Basel). 2025 Feb 27. pii: 106. [Epub ahead of print]13(3):
      This review highlights the key molecular and cellular mechanisms contributing to aging, such as DNA damage, mitochondrial dysfunction, telomere shortening, protein dysfunction, and defective autophagy. These biological mechanisms are involved in various oral health conditions prevalent in the elderly, including periodontal disease, oral cancer, xerostomia, dental caries, and temporomandibular joint disorders. Exosomes generated by mesenchymal stem cells possess substantial therapeutic potential. These exosomes are nanosized extracellular vesicles derived from cells and are involved in essential intercellular communication and tissue homeostasis. The exosome-based therapies proved superior to traditional cell-based approaches, due to lower immunogenicity, ease of storage, and avoidance of complications associated with cell transplantation. Furthermore, the diagnostic potential of exosomes as non-invasive biomarkers for aging processes and age-related oral diseases offers insights into disease diagnosis, staging, and monitoring. Among the challenges and future perspectives of translating exosome research from preclinical studies to clinical applications is the need for standardized procedures to fully harness the therapeutic and diagnostic capabilities of exosomes.
    Keywords:  MSCs; aging; diagnosis; exosomes; oral; para-oral; therapy
    DOI:  https://doi.org/10.3390/dj13030106
  40. Ageing Res Rev. 2025 Mar 22. pii: S1568-1637(25)00078-9. [Epub ahead of print]108 102732
      Mitochondria, as central regulators of cellular processes such as energy production, apoptosis, and metabolic homeostasis, are essential to cellular function and health. The maintenance of mitochondrial integrity, especially through mitophagy-the selective removal of impaired mitochondria-is crucial for cellular homeostasis. Dysregulation of mitochondrial function, dynamics, and biogenesis is linked to neurodegenerative and metabolic diseases, notably Alzheimer's disease (AD), which is increasingly recognized as a metabolic disorder due to its shared pathophysiologic features: insulin resistance, oxidative stress, and chronic inflammation. In this review, we highlight recent advancements in pharmacological interventions, focusing on agents that modulate mitophagy, mitochondrial uncouplers that reduce oxidative phosphorylation, compounds that directly scavenge reactive oxygen species to alleviate oxidative stress, and molecules that ameliorate amyloid beta plaque accumulation and phosphorylated tau pathology. Additionally, we explore dietary and lifestyle interventions-MIND and ketogenic diets, caloric restriction, physical activity, hormone modulation, and stress management-that complement pharmacological approaches and support mitochondrial health. Our review underscores mitochondria's central role in the pathogenesis and potential treatment of neurodegenerative and metabolic diseases, particularly AD. By advocating for an integrated therapeutic model that combines pharmacological and lifestyle interventions, we propose a comprehensive approach aimed at mitigating mitochondrial dysfunction and improving clinical outcomes in these complex, interrelated diseases.
    Keywords:  Aging; Alzheimer’s disease; Diabetes; Metabolic disorders; Mitochondrial dysfunction; Mitophagy; Oxidative stress
    DOI:  https://doi.org/10.1016/j.arr.2025.102732
  41. Macromol Biosci. 2025 Mar 25. e2500031
      With the aging population, fitness issues, poor bone healing, and high infection rates are associated with bone fractures and other bone diseases. Nevertheless, traditional approaches and materials struggle to treat orthopedic diseases by loading exogenous stem cells, growth factors, or merely structurally simulating the bone periosteum. The advancement of biomedical materials has become critical in addressing the challenges associated with bone tissue regeneration, encompassing a range of conditions including bone wounds, inflammation, infections, fractures, and the degenerative effects of aging or metabolic disorders. Recently, polymer-based piezoelectric materials have emerged as a promising avenue for enhancing regenerative processes. These materials possess unique electrical properties that can stimulate cellular activities and promote healing, making them particularly suitable for bone tissue engineering applications. This review aims to delineate the multifaceted role of polymer-based piezoelectric materials in treating various bone-related ailments, highlighting their potential for active regeneration actively and pointing out the challenges and future research directions for piezoelectric materials in regenerative medicine for bone tissue engineering. By integrating insights from materials science and biomedical engineering to develop more effective strategies for managing bone tissue injuries and disorders, ultimately enhancing bone healing, promoting osseointegration, and accelerating tissue regeneration.
    Keywords:  bone tissue engineering; orthopedic diseases; piezoelectric materials; polymers; scaffolds
    DOI:  https://doi.org/10.1002/mabi.202500031
  42. J Gerontol A Biol Sci Med Sci. 2025 Mar 22. pii: glaf004. [Epub ahead of print]
      The active peptide hormone Ang II (angiotensin II) mediates the vast majority of the RAS (renin-angiotensin system) action, mainly through activation of AT1R (Angiotensin II type-1 receptor). AT1R expression peaks in newborn males and decreases toward the adult age, and it is shown to exhibit an inhibitory effect on hCG (human chorionic gonadotropin)-stimulated steroidogenesis in LCs (Leydig cells), as well as an promoting effect on smooth muscle and endothelial cell senescence. However, whether hyperactivation of the AT1R signaling exerts any effects on Leydig cell senescence, which could provide insights into hypogonadism mechanisms for aging males, remains unexplored. We herein reported that AT1R expression was significantly upregulated in aged human and rat testes. Transgenic overexpression of AT1R in LCs mimicked multiple late-onset hypogonadism phenotypes, including acceleration of Leydig cell senescence, defective steroidogenesis and spermatogenesis, and increased inflammation and oxidative stress. One of the core biochemical events underpinning AT1R action was the AT1R-induced enhancement of the interaction between MDM2 (murine double minute 2) and the p65 subunit of NF-κB (nuclear factor-kappaB), consequently augmenting polyubiquitination and activation of p65, in a p38-dependent manner. Conversely, repression of AT1R activity ameliorated Leydig cell senescence and rescued testicular steroidogenesis in old rats. Together, forced expression of AT1R within the testicular interstitium potentiates aging-related traits in LCs, thereby leading to fertility impairment with defective steroidogenesis and spermatogenesis in male rodents. Our systematic analysis also indicates that blocking the Ang II/AT1R signal might be beneficial in intervening disorders of late-onset hypogonadism in old males.
    Keywords:  Leydig cells; NF-κB; angiotensin; p38; senescence; ubiquitination
    DOI:  https://doi.org/10.1093/gerona/glaf004
  43. J Nutr Biochem. 2025 Mar 20. pii: S0955-2863(25)00067-1. [Epub ahead of print] 109904
       SCOPE: Gut microbiota preservation or rational manipulation is a key condition for healthy longevity and a promising strategy to prevent neurodegenerations exploiting the gut-brain axis, with a key role of prebiotics and probiotics. Whether their combination in a functional food can provide a synergistic effect to the host remains controversial.
    METHODS AND RESULTS: To fill this gap, we supplemented the diet of 3xTg-AD Alzheimer's disease mice with a red lentils (prebiotic)-based cookie enriched with neuroprotective probiotics and we performed behavioural, biochemical and molecular tests. Chronic consumption of this synbiotic preparation (functional cookie) preserved cognition, reduced amyloid load, improved glucose and lipid homeostasis and diminished oxidation and inflammation related damages compared to animals receiving a classic cookie (standard recipe). The synergistic effect was indicated by significantly higher glucose insulinotropic polypeptide concentrations in the functional cookie group compared to probiotic group. Moreover, Ruminoclostridium sp KB18 and Ruminicoccus decreased in the gut of mice supplemented with the functional cookie, partially explaining the improved short-term memory upon treatments and substantiating the combined use over individual components.
    CONCLUSION: This synbiotic innovative snack represents a prototype of a simple and affordable dietary approach to promote healthy aging and prevent or delay the onset of neurodegenerations.
    Keywords:  functional cookie; gut-brain axis; healthy aging; neurodegeneration; synbiotic
    DOI:  https://doi.org/10.1016/j.jnutbio.2025.109904
  44. Geroscience. 2025 Mar 28.
      Many of the "hallmarks of aging" involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation, and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver, and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8 to 25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. Within the brain, SIRT1 and MAPK8 were reduced in CA3 of kTRF-fed rats. Additionally, IGF1 expression was significantly upregulated in the CA1 of cTRF-fed rats, but this effect was ameliorated in the kTRF fed group. AKT and FOXO1 expression were significantly reduced in kTRF-fed rats within liver. Interestingly, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance, and FOXO1 expression was higher in the CA3 of AL-fed rats correlated with the poorest cognitive performance. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.
    Keywords:  Aging; Brain; Diet; Liver; Metabolism; Muscle
    DOI:  https://doi.org/10.1007/s11357-025-01632-7
  45. Cell Death Dis. 2025 Mar 25. 16(1): 203
      Senescence is a non-proliferative cellular state derived from aging or in response to exogenous insults, such as those that cause DNA damage. As a result of cancer treatments like cisplatin, certain tumor cells may undergo senescence. However, rather than being beneficial for patients, this is detrimental because these cells might proliferate again under specific conditions and, more importantly, because they synthesize and secrete molecules that promote the proliferation of nearby cells. Therefore, to achieve complete tumor remission, it is necessary to develop senolytic compounds to eliminate senescent cells. Here, we studied the role of βTrCP1 in cell proliferation and senescence and found that lentiviral overexpression of βTrCP1 induces the death of senescent cells obtained after cisplatin treatment in both two-dimensional cell cultures and tumorspheres. Mechanistically, we demonstrated that overexpression of βTrCP1 triggers proteasome-dependent degradation of p21 CIP1, allowing damaged cells to progress through the cell cycle and consequently die. Furthermore, we identified nucleophosmin 1 (NPM1) as the intermediary molecule involved in the effect of βTrCP1 on p21 CIP1. We determined that increased amounts of βTrCP1 partially retains NPM1 in the nucleoli, preventing it from associating with p21 CIP1, thus leaving it unprotected from degradation by the proteasome. These results have allowed us to discover a potential new target for senolytic drugs, as retaining NPM1 in the nucleoli under senescent conditions induces cell death.
    DOI:  https://doi.org/10.1038/s41419-025-07556-6
  46. J Cosmet Dermatol. 2025 Apr;24(4): e70066
       BACKGROUND: Aging is associated with fat atrophy and fibrosis with loss of adipocyte differentiation from preadipocytes. New approaches to this loss involve agents that can renew the proliferative and differentiative capacities of preadipocytes with the aim of creating new healthy adipose tissue that secrete adipokines that positively impact on skin health.
    MATERIAL & METHODS: We investigated the effect of Magnolol (ML), a naturally derived compound, on human primary pre-adipocyte viability and proliferation as well as adipogenic gene expression and increase in lipid production. Cell proliferation was assessed using fluorescent signaling, and adipocyte differentiation was monitored by following morphological and microscopic changes. RNA purification and real-time PCR were undertaken to examine gene expression changes, and Oil red O staining was used to confirm adipose cell transformation. Adipokine expression, in particular adiponectin quantification, was also undertaken.
    RESULTS: Magnolol, at a relatively low concentration, demonstrated clear adipogenic activity: with a significant increase in preadipocyte proliferation after 48 h and a significant accumulation of adipocytes as demonstrated by oil red staining. Increased gene expression of PLN1 and FABP4 and a significant increase in adiponectin protein expression was demonstrated.
    CONCLUSION: Magnolol stimulates preadipocyte proliferation and conversion to adipokine-producing adipocytes. This has the potential for a positive skin health and volumizing effect if used in a topical formulation.
    Keywords:  CCAAT/enhancer‐binding protein alpha (c/EBPα); adipogenesis; adiponectin; fatty acid binding protein 4 (FABP4); magnolol (ML); perilipin (PLIN); peroxisome proliferator‐activated receptor (PPARγ); subcutaneous white adipose tissue (sWAT)
    DOI:  https://doi.org/10.1111/jocd.70066
  47. Nat Aging. 2025 Mar 24.
      Aging is reflected by genome-wide DNA methylation changes, which form the basis of epigenetic clocks, but it is largely unclear how these epigenetic modifications are regulated and whether they directly affect the aging process. In this study, we performed epigenetic editing at age-associated CpG sites to explore the consequences of interfering with epigenetic clocks. CRISPR-guided editing targeted at individual age-related CpGs evoked genome-wide bystander effects, which were highly reproducible and enriched at other age-associated regions. 4C-sequencing at age-associated sites revealed increased interactions with bystander modifications and other age-related CpGs. Subsequently, we multiplexed epigenetic editing in human T cells and mesenchymal stromal cells at five genomic regions that become either hypermethylated or hypomethylated upon aging. While targeted methylation seemed more stable at age-hypermethylated sites, both approaches induced bystander modifications at CpGs with the highest correlations with chronological age. Notably, these effects were simultaneously observed at CpGs that gain and lose methylation with age. Our results demonstrate that epigenetic editing can extensively modulate the epigenetic aging network and interfere with epigenetic clocks.
    DOI:  https://doi.org/10.1038/s43587-025-00841-1
  48. Mol Metab. 2025 Mar 22. pii: S2212-8778(25)00037-7. [Epub ahead of print] 102130
       BACKGROUND: Cellular senescence (CS) is a key aging process that leads to irreversible cell cycle arrest and an altered secretory phenotype. In skeletal muscle (SkM), the accumulation of senescent cells contributes to sarcopenia. Despite exercise being a known intervention for maintaining SkM function and metabolic health, its effects on CS remain poorly understood.
    OBJECTIVES: This study aimed to investigate the impact of exercise on CS in human SkM by analyzing muscle biopsies from young, normal-weight individuals and middle-aged individuals with obesity, both before and after exercise intervention.
    METHODS: Muscle biopsies were collected from both groups before and after an exercise intervention. CS markers, insulin sensitivity (measured with euglycemic clamp), and satellite cell markers were analyzed. Additionally, in vitro experiments were conducted to evaluate the effects of cellular senescence on human satellite cells, focusing on key regulatory genes and insulin signaling.
    RESULTS: Individuals with obesity showed significantly elevated CS markers, along with reduced expression of GLUT4 and PAX7, indicating impaired insulin action and regenerative potential. Exercise improved insulin sensitivity, reduced CS markers, and activated satellite cell response in both groups. In vitro experiments revealed that senescence downregulated key regulatory genes in satellite cells and impaired insulin signaling by reducing the Insulin Receptor β-subunit.
    CONCLUSIONS: These findings highlight the role of CS in regulating insulin sensitivity in SkM and underscore the therapeutic potential of exercise in mitigating age- and obesity-related muscle dysfunction. Targeting CS through exercise or senolytic agents could offer a promising strategy for improving metabolic health and combating sarcopenia, particularly in at-risk populations.
    Keywords:  Aging; Cellular senescence; Exercise intervention; Obesity; Satellite cells; Skeletal muscles
    DOI:  https://doi.org/10.1016/j.molmet.2025.102130