bims-caglex 2025-06-01 papers

bims-caglex

Biomed News

on Cellular aging and life extension

Issue of 2025–06–01
24 papers selected by
Mario Alexander Guerra Patiño, Universidad Antonio Nariño

Telomeres as hallmarks of iPSC aging: A review on telomere dynamics during stemness and cellular reprogramming.
Causality of Aging Hallmarks.
Systemic aging delay and anti-aging therapy using allogeneic stem cells.
Metformin and Dietary Restriction Counteract Aging via Reducing m6A-Dependent Stabilization of Methionine Synthase mRNA in Brachionus asplanchnoidis (Rotifera).
Advancing T-cell immunotherapy for cellular senescence and disease: Mechanisms, challenges, and clinical prospects.
Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches.
Age-associated decline of Coenzyme A leads to intestinal stem cells dysfunction via disturbing iron homeostasis.
The Combination of Two Small Molecules Improves Neurological Parameters and Extends the Lifespan of C3H Strain Female Mice.
Harnessing the power of stem cell-derived exosomes: a rejuvenating therapeutic for skin and regenerative medicine.
ElixirSeeker: A Machine Learning Framework Utilizing Fusion Molecular Fingerprints for the Discovery of Lifespan-Extending Compounds.
In-silico Evaluation of Aging-Related Interventions Using Omics Data and Predictive Modeling.
Geroprotective applications of oleuropein and hydroxytyrosol through the hallmarks of ageing.
Senolytic effects of a modified Gingerenone A.
Epigenetic Clocks and EpiScore for Preventive Medicine: Risk Stratification and Intervention Models for Age-Related Diseases.
Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.
Multi-Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single-Blinded Randomized Placebo-Controlled Therapeutic Plasma Exchange.
The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.
Extracellular vesicles in age-related diseases: disease pathogenesis, intervention, and biomarker.
Nucleotides as an Anti-Aging Supplementation in Older Adults: A Randomized Controlled Trial (TALENTs study).
Circadian Gene BMAL1 Regulation of Cellular Senescence in Thyroid Aging.
From current landscape to future horizon in stem cell therapy for tissue regeneration and wound healing: bridging the gap.
Unraveling senescence in cancer: mechanistic complexities and therapeutic opportunities.
Cationic microbubbles loading shFOXO4/SDF1 rejuvenate the aged heart and alleviate myocardial ischemia-reperfusion injury in the elderly.
IDO1 improves postischemic neovascularization in aged mice by boosting endothelial NAD+ de novo synthesis and curbing endothelial senescence.

Ageing Res Rev. 2025 May 23. pii: S1568-1637(25)00119-9. [Epub ahead of print]109 102773

Telomeres as hallmarks of iPSC aging: A review on telomere dynamics during stemness and cellular reprogramming.

Carlota Tavares-Marcos, Magda Correia, Bruno Bernardes de Jesus.

  Telomeres, the protective ends of chromosome, are key to tissue repair and regeneration. Telomere shortening is linked to aging and age-related disorders, while excessive telomerase activity may support tissue regeneration or transformation. Some of the functions of telomeres and telomerase may be mediated by its important role in the process of stemness. Active telomerase, and subsequent telomerase-dependent telomere extension, supports stem-cells self-renewal and pluripotency - essential for tissue healing. During cellular reprogramming, differentiated cells are converted into induced pluripotent stem cells (iPSCs), which resemble embryonic stem cells. During iPSC derivation, telomere length is reset, enhancing iPSCs' regenerative potential. During this process, incomplete telomerase activation and telomere extension can lead to genomic instability and/or haltered cell functionality. Understanding the intricate relation of telomeres, telomerase and stemness may be critical when designing novel cell-based therapies targeting degenerative diseases or to unlock strategies to delay aging. Here, we explore the recent bibliography linking these areas, raising awareness of their important when designing novel breakthroughs in health and longevity.

Keywords:  Cellular reprogramming; ESC; IPSC; Telomerase; Telomeres

DOI:  https://doi.org/10.1016/j.arr.2025.102773
Aging Dis. 2025 May 20.

Causality of Aging Hallmarks.

Bilu Huang, Xiaowen Hu.

This article emphasizes the causal relationship in the mechanisms of aging, asserting that among the twelve hallmarks of aging, only telomere shortening is the cause of aging. The "Telomere DNA and ribosomal DNA co-regulation model for cell senescence" suggests that the shortening of telomeres and rDNA arrays can mediate various hallmarks of aging through the P53 pathway. Therefore, the best way to reverse aging and significantly extend lifespan is to increase the length of telomeres and rDNA arrays in adult stem cells within tissues.

DOI: https://doi.org/10.14336/AD.2025.0541
Korean J Fam Med. 2025 May;46(3): 127-136

Systemic aging delay and anti-aging therapy using allogeneic stem cells.

Seongho Han, Sung-Whan Kim.

  Allogeneic stem cells derived from umbilical cord tissue, placenta, and umbilical cord blood have shown potential in treating delayed systemic aging and aging-related diseases. Aging induces cellular senescence, oxidative stress, chronic inflammation, and stem cell depletion, all of which contribute to tissue damage and functional decline. Recent advances in regenerative medicine suggest that allogeneic stem cells can mitigate these aging processes through immunomodulation and tissue regeneration. In particular, umbilical cord-derived mesenchymal stem cells have gained attention for clinical applications owing to their strong immunomodulatory properties and low immunogenicity. These cells can repair damaged tissues and enhance metabolic and cognitive function by secreting various cytokines, growth factors, and exosomes, offering potential treatment for aging-related conditions such as osteoporosis and neurodegenerative disorders. Both clinical and preclinical studies indicate that allogeneic stem cells play a critical role in alleviating these diseases, including osteoporosis, osteoarthritis, cardiovascular diseases, and neurodegenerative disorders. Despite their therapeutic potential, challenges remain, such as immune compatibility, long-term safety, and the lack of standardized protocols for large-scale production. This review outlines the biological mechanisms by which allogeneic stem cells contribute to delayed aging, summarizes current clinical research, and explores future prospects. Allogeneic stem cells may offer novel strategies for delaying aging and extending lifespan.

Keywords:  Allogeneic Transplantation; Anti-aging; Mesenchymal Stem Cells; Stem Cells; Umbilical Cord

DOI:  https://doi.org/10.4082/kjfm.25.0080
Aging Cell. 2025 May 27. e70113

Metformin and Dietary Restriction Counteract Aging via Reducing m6A-Dependent Stabilization of Methionine Synthase mRNA in Brachionus asplanchnoidis (Rotifera).

Yu Zhang, Xiaojie Liu, Hairong Lian, Yanchao Chai, Yang Zhou, Dongqi Kan, Jilong Ren, Cui Han, Jiaxin Yang.

  Metformin, a medication primarily used to treat diabetes, has gained attentions for its potential antiaging properties. Although the metabolic and cellular pathways behind its longevity effects have been widely studied, few studies have explored the epigenetic regulatory effects of metformin, which are a crucial factor in aging processes. In this study, we examined the antiaging effects of metformin using the Brachionus rotifer as a model, focusing on the regulation of mRNA N6-methyladenosine (m6A), a key RNA modification involved in mRNA stability, translation, and splicing. We found metformin significantly extended the rotifers' lifespan, mimicking the effects of dietary restriction (DR), a well-established antiaging intervention. Both metformin and DR modulate m6A dynamics, with a notable reduction in the m6A modification of MTR (5-methyltetrahydrofolate-homocysteine methyltransferase). This reduction led to decreased MTR expression and lowered levels of S-adenosylmethionine (SAM), a critical metabolite in the one-carbon cycle. We propose that the downregulation of MTR through m6A modification limits methionine synthesis and imposes methionine restriction, a key factor in promoting longevity. Our findings reveal a novel epitranscriptional regulatory model by which metformin and DR modulate m6A to extend lifespan, highlighting MTR as a central regulator of aging and suggesting potential therapeutic strategies for healthy aging through m6A and methionine metabolism.

Keywords:  MTR; antiaging; dietary restriction; m6A; metformin; methionine metabolism; rotifer

DOI:  https://doi.org/10.1111/acel.70113
Ageing Res Rev. 2025 May 22. pii: S1568-1637(25)00129-1. [Epub ahead of print]109 102783

Advancing T-cell immunotherapy for cellular senescence and disease: Mechanisms, challenges, and clinical prospects.

Jizhun Wu, Lu Zhang, Zihan Zhao, Yuping Liu, Zhengxing Li, Xiaohang Feng, Lin Zhang, Xiang Yao, Jun Du, Liang Chen, Zhuolong Zhou.

  Cellular senescence is a complex biological process with a dual role in tissue homeostasis and aging-related pathologies. Accumulation of senescent cells promotes chronic inflammation, tissue dysfunction, age-related diseases, and tumor suppression. Recent advancements in immunotherapy have positioned T cell-based approaches as precision tools for the targeted clearance of senescent cells, offering a novel avenue for anti-aging interventions. This review explores the molecular mechanisms underlying cellular senescence, focusing on its immunogenic features and interactions with T cells, including T-cell activation, antigen recognition, modulation of tumor microenvironment (TME), and immune evasion strategies. Innovations such as chimeric antigen receptor (CAR)-T cells, immune checkpoint therapies, and SASP-neutralizing approaches are highlighted as breakthrough strategies for enhancing senescent cell eradication. The integration of multi-omics and artificial intelligence is further catalyzing the development of personalized therapies to amplify immune surveillance and tissue rejuvenation. Clinically, T cell-based interventions hold promise for mitigating age-related pathologies and extending healthspan, yet challenges remain in optimizing target specificity, countering immunosuppressive niches, and overcoming immune senescence in aging populations. This review synthesizes current advances and challenges, highlighting the potential of T cell immunotherapy as a cornerstone of anti-aging medicine and emphasizing the need for interdisciplinary innovation to translate preclinical findings into transformative therapies for aging and age-related diseases.

Keywords:  Aging and age-related diseases; CAR-T cells; Cellular senescence; Immune surveillance; Senotherapy; T-cell immunotherapy

DOI:  https://doi.org/10.1016/j.arr.2025.102783
Aging Cell. 2025 May 28. e70114

Intermittent Supplementation With Fisetin Improves Physical Function and Decreases Cellular Senescence in Skeletal Muscle With Aging: A Comparison to Genetic Clearance of Senescent Cells and Synthetic Senolytic Approaches.

Kevin O Murray, Sophia A Mahoney, Katelyn R Ludwig, Jill H Miyamoto-Ditmon, Nicholas S VanDongen, Nirad Banskota, Allison B Herman, Douglas R Seals, Robert T Mankowski, Matthew J Rossman, Zachary S Clayton.

  Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice. The improvements in frailty and grip strength in old mice were accompanied by favorable modulation of the skeletal muscle transcriptome, including lower abundance of cellular senescence-related genes (e.g., Cdkn1a and Ddit4). Improvements in frailty and grip strength with fisetin were comparable to those observed with genetic-based clearance of excess p16+ senescent cells and treatment with ABT-263. Taken together, our findings provide proof-of-concept support for fisetin as a senolytic strategy to improve physical function with aging.

Keywords:  flavonoid; motor function; natural senolytic; senescence associated secretory phenotype; skeletal muscle senescence; transcriptome

DOI:  https://doi.org/10.1111/acel.70114
PLoS Genet. 2025 May 30. 21(5): e1011704

Age-associated decline of Coenzyme A leads to intestinal stem cells dysfunction via disturbing iron homeostasis.

Zhiming Liu, Gang Du, Yi Chen, Haiyang Chen.

The decline in adult stem cell performance is closely linked to tissue malfunction and the rising incidence of age-related diseases. To investigate the molecular basis of these impairments, our screening strategy identified reduced activity in the pantothenate/coenzyme A (CoA) pathway within aged ISCs. Furthermore, exogenous CoA supplementation restructured ISC metabolic pathways, reversing age-induced hyperproliferation and intestinal dysfunction, and thus extending Drosophila lifespan by curbing excessive iron accumulation in ISCs. These findings uncover a new mechanism of stem cell aging and propose that pantothenate and CoA could be potential therapeutic targets for treating age-related diseases and enhancing healthy aging in humans.

DOI: https://doi.org/10.1371/journal.pgen.1011704
Brain Behav. 2025 Jun;15(6): e70573

The Combination of Two Small Molecules Improves Neurological Parameters and Extends the Lifespan of C3H Strain Female Mice.

Maria Vedunova, Olga Borysova, Elena Mitroshina, Ivan Morgunov, Alexander Fedintsev, Alexey Moskalev.

   OBJECTIVES: Targeting partial cellular reprogramming pathways through specific small molecule combinations holds promise for lifespan extension in model organisms. Chemical cocktails like RepSox and tranylcypromine (TCP) may induce beneficial age-related changes without the risks of full reprogramming. This study investigated the effects of RepSox and TCP on neurological markers, physical activity, skeletal health, and survival in aging C3H female mice.
METHODS: Female C3H mice were divided into two age groups: "old" (16-20 months) and "senior" (10-13 months). They received intraperitoneal injections of RepSox (5 mg/kg) and TCP (3 mg/kg) or DMSO (control) every 72 h for 30 days. Physiological state, neurological scores, open field test performance, skeletal deformation, and survival were assessed. Histological analyses of organs (brain, liver, heart, kidneys, lungs, muscles) were performed post-treatment. Statistical analyses included Mann-Whitney tests, mixed-effects linear regression, Kaplan-Meier survival analysis, and the Gao-Allison test.
FINDINGS: In the "old" group, treated mice showed enhanced neurological status, fur and skeletal health, and increased cortical angiogenesis, though with some adverse histological changes in the liver and brain. In the "senior" group, treated mice displayed a plateau in mortality after month seven, while deaths continued in controls. Although overall survival was not significantly different, maximum lifespan significantly increased in treated mice (p = 0.039, Gao-Allison test). Histological findings revealed localized adaptive changes rather than major toxic effects. These results suggest that the combination of RepSox and TCP exerts protective effects on aging phenotypes and may potentially slow systemic aging processes in C3H mice.

Keywords:  neurological aging; osteoporosis; partial reprogramming; survival

DOI:  https://doi.org/10.1002/brb3.70573
3 Biotech. 2025 Jun;15(6): 184

Harnessing the power of stem cell-derived exosomes: a rejuvenating therapeutic for skin and regenerative medicine.

Gracy Seth, Siddharth Singh, Geetansh Sharma, Divyesh Suvedi, Dinesh Kumar, Rupak Nagraik, Avinash Sharma.

  Exosomes are small extracellular vesicles produced by most cell types and contain proteins, lipids, and nucleic acids (non-coding RNAs, mRNA, and DNA) that can be released by donor cells to influence the function of recipient cells. Skin photoaging is the premature aging of skin structures caused by prolonged exposure to ultraviolet (UV), as demonstrated by depigmentation, roughness, rhytides, elastosis, and precancerous alterations. Exosomes are associated with aging processes such as oxidative damage, inflammation, and senescence. Exosomes' anti-aging properties have been linked to various in vitro and preclinical investigations. There are still several unanswered questions about the use of MSC exosomes for skin rejuvenation, despite encouraging results. Uncertainty surrounds the precise processes by which exosomes stimulate the creation of collagen, skin tissue via a variety of mechanisms, including reduced matrix metalloproteinase (MMP) expression, increased collagen and elastin production, and modulation of intracellular signaling pathways and intercellular communication. These findings suggest the therapeutic potential of exosomes in skin aging. This review provides information on the molecular mechanisms and consequences of exosome anti-aging.

Keywords:  Anti-aging; Exosomes; Metalloproteinase; Molecular pathways; Stem cells

DOI:  https://doi.org/10.1007/s13205-025-04345-y
Aging Cell. 2025 May 26. e70116

ElixirSeeker: A Machine Learning Framework Utilizing Fusion Molecular Fingerprints for the Discovery of Lifespan-Extending Compounds.

Yan Pan, Hongxia Cai, Fang Ye, Wentao Xu, Zhihang Huang, Jingyuan Zhu, Yiwen Gong, Yutong Li, Anastasia Ngozi Ezemaduka, Shan Gao, Shunqi Liu, Guojun Li, Hao Li, Jing Yang, Junyu Ning, Bo Xian.

  Despite the growing interest in developing anti-aging drugs, high costs and low success rates of traditional drug discovery methods pose significant challenges. Aging is a complex biological process associated with numerous diseases, making the identification of compounds that can modulate aging mechanisms critically important. Accelerating the discovery of potential anti-aging compounds is essential to overcome these barriers and enhance lifespan and healthspan. Here, we present ElixirSeeker, a machine learning framework designed to maximize feature capture of lifespan-extending compounds through multi-fingerprint fusion mechanisms. Utilizing this approach, we identified several promising candidate drugs from external compound databases. We tested the top six hits in Caenorhabditis elegans and found that four of these compounds-including Praeruptorin C, Polyphyllin VI, Thymoquinone, and Medrysone-extended the organism's lifespan. This study demonstrates that ElixirSeeker effectively accelerates the identification of viable anti-aging compounds, potentially reducing costs and increasing the success rate of drug development in this field.

Keywords:   Caenorhabditis elegans ; aging; drug discovery; lifespan‐extending; machine learning

DOI:  https://doi.org/10.1111/acel.70116
Ageing Res Rev. 2025 May 23. pii: S1568-1637(25)00123-0. [Epub ahead of print] 102777

In-silico Evaluation of Aging-Related Interventions Using Omics Data and Predictive Modeling.

Georg Fuellen, Daniel Palmer, Claudia Fruijtier, Roberto A Avelar.

  A major challenge in aging research is identifying interventions that can improve lifespan and health and minimize toxicity. Clinical studies cannot consider decades-long follow-up periods, and therefore, in-silico evaluations using omics-based surrogate biomarkers are emerging as key tools. However, many current approaches train predictive models on observational data, rather than on intervention data, which can lead to biased conclusions. Yet, the first classifiers for lifespan extension by compounds are now available, learned on intervention data. Here, we review evaluation methodologies and we prioritize training on intervention data whenever available, highlight the importance of safety and toxicity assessments, discuss the role of standardized benchmarks, and present a range of feature processing and predictive modeling approaches. We consider linear and non-linear methods, and automated machine learning workflows. We conclude by emphasizing the need for explainable and reproducible strategies, the integration of safety metrics, and the careful validation of predictors based on interventional benchmarks.

Keywords:  gene expression; interpretable features; longevity interventions; predictive modeling; toxicity/safety

DOI:  https://doi.org/10.1016/j.arr.2025.102777
Geroscience. 2025 May 27.

Geroprotective applications of oleuropein and hydroxytyrosol through the hallmarks of ageing.

Anna Calabrò, Anna Aiello, Paula Silva, Calogero Caruso, Giuseppina Candore, Giulia Accardi.

  Geroprotectors are compounds that target the underlying mechanisms of ageing to delay the onset of age-related diseases and extend both lifespan and health span. As ageing is driven by the accumulation of cellular damage, DNA instability, epigenetic changes, mitochondrial dysfunction, and chronic inflammation, the concept of geroprotection focuses on compounds that can mitigate these processes. Oleuropein (OLE) and its derivative hydroxytyrosol (HT), both phenolic molecules derived from Olea europaea (olive tree), have gained significant attention as potential geroprotectors due to their potent antioxidant and anti-inflammatory properties. These phytochemicals, central to the Mediterranean diet, activate key molecular pathways such as nuclear factor erythroid 2-related factor 2, reducing oxidative stress and modulating inflammatory responses. Through these mechanisms, OLE and HT help counteract inflammageing, a critical factor in age-related dysfunction. This review highlights the role of OLE and HT as geroprotective agents, emphasising their ability to target the hallmarks of ageing and their potential to improve health span by slowing the progression of age-related conditions. With proven efficacy in various biological models, these compounds represent promising tools in the ongoing search for strategies to enhance the quality of life in ageing populations.

Keywords:  Ageing; Geroprotectors; Hydroxytyrosol; Inflammageing; Oleuropein

DOI:  https://doi.org/10.1007/s11357-025-01697-4
NPJ Aging. 2025 May 30. 11(1): 45

Senolytic effects of a modified Gingerenone A.

Ruin Moaddel, Chad Sanehira, Gregory Keyes, Chang-Yi Cui, Reza Ahmadkhania, Julián Candia, Nathan L Price, Sarah Eckroth, Bryce Middleton, Mohammed Khadeer, Caio H Mazucanti, Ross A McDevitt, Myriam Gorospe, Rafael de Cabo, Josephine M Egan, Christopher E Ramsden, Luigi Ferrucci.

Senescent cells accumulate with aging and are associated with several age-associated diseases and functional declines. Eliminating senescent cells with senolytics improves aging phenotypes in mouse models and may improve the health of people with chronic diseases. To date, very few senotherapeutic (senolytics and senomorphics) compounds have been identified. In a recent study, we reported that gingerenone A (GinA) has a senolytic effect via mechanisms including the activation of caspase-3 activity and apoptotic cell death. In this study, we investigated whether GinA has senotherapeutic properties in a mouse model of senescence. Moreover, we modified GinA with eicosapentaenoic acid (EPA) esters (GinA-EPA) or docosahexaenoic acid (DHA) esters (GinA-DHA) to generate modified gingerenone A (modGinA) that could enhance GinA effects. We found that both GinA and modGinA induced biochemical and histological changes consistent with anti-inflammatory, senolytic, and senomorphic effects, leading to improved metabolic and mitochondrial functions.

DOI: https://doi.org/10.1038/s41514-025-00230-3
J Clin Med. 2025 May 21. pii: 3604. [Epub ahead of print]14(10):

Epigenetic Clocks and EpiScore for Preventive Medicine: Risk Stratification and Intervention Models for Age-Related Diseases.

Hidekazu Yamada.

  Aging is the primary risk factor for chronic diseases such as cardiovascular disease, cancer, and dementia. However, chronological age alone fails to capture individual variability in aging trajectories and disease susceptibility. Recent advances in epigenetic clocks-DNA methylation-based models that estimate biological age-have opened new possibilities for personalized and preventive medicine. This review explores the clinical potential of epigenetic clocks and EpiScores, composite biomarkers that predict health risks and physiological status. We present a comparative evaluation of widely used epigenetic clocks, including Horvath, GrimAge, PhenoAge, and DunedinPACE, and summarize their predictive performance for mortality, cognitive decline, and cardiovascular outcomes. EpiScores linked to inflammation, glycemic control, and immunosenescence are highlighted as tools for stratified risk assessment. When integrated with multi-omics data and electronic health records, these measures enhance the precision of population health management. Special emphasis is placed on applications in longevity clinics and anti-aging clinics, community-based care, and national health checkup systems. We also explore global standardization efforts and ethical considerations, as well as Japan's unique initiatives-including the "Aging Measurement" project at the Osaka-Kansai Expo 2025. Furthermore, we propose the development of a Global Health and Aging Index that integrates the biological, functional, and subjective dimensions of aging, aligned with the WHO concept of Intrinsic Capacity. In conclusion, epigenetic clocks and EpiScores represent transformative tools for shifting from reactive treatment to proactive health optimization, and from chronological to biological metrics in aging science and public health policy.

Keywords:  EpiScore; aging; biological age; epigenetic clock; multi-omics; preventive medicine; public health

DOI:  https://doi.org/10.3390/jcm14103604
Nat Commun. 2025 May 27. 16(1): 4909

Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila.

Yao Zhang, Peng Ma, Saifei Wang, Shuxin Chen, Hansong Deng.

Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa2+) levels were elevated while mitochondrial calcium (MitoCa2+) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa2+ was decoupled from the intracellular calcium network and whether the reduction of MitoCa2+ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa2+ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa2+ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa2+ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.

DOI: https://doi.org/10.1038/s41467-025-60196-4
Aging Cell. 2025 May 27. e70103

Multi-Omics Analysis Reveals Biomarkers That Contribute to Biological Age Rejuvenation in Response to Single-Blinded Randomized Placebo-Controlled Therapeutic Plasma Exchange.

Matias Fuentealba, Dobri Kiprov, Kevin Schneider, Wei-Chieh Mu, Prasanna Ashok Kumaar, Herbert Kasler, Jordan B Burton, Mark Watson, Heather Halaweh, Christina D King, Zehra Stara Yüksel, Chelo Roska-Pamaong, Birgit Schilling, Eric Verdin, David Furman.

  We conducted a randomized, placebo-controlled trial to assess the safety and biological age (BA) effects of various therapeutic plasma exchange (TPE) regimens in healthy adults over 50. Participants received bi-weekly TPE with or without intravenous immunoglobulin (IVIG), monthly TPE, or placebo. Randomization was based on entry date, and treatments were blinded to maintain objectivity. Primary objectives were to assess long-term TPE safety and changes in biological clocks. Secondary goals included identifying optimal regimens. Exploratory analyses profiled baseline clinical features and longitudinal changes across the epigenome, proteome, metabolome, glycome, immune cytokines, iAge, and immune cell composition. We demonstrate in 42 individuals randomized to various treatment arms or placebo that long-term TPE was found to be safe, with only two adverse events requiring discontinuation and one related to IVIG. TPE significantly improved biological age markers, with 15 epigenetic clocks showing rejuvenation compared to placebo (FDR < 0.05). Biweekly TPE combined with intravenous immunoglobulin (TPE-IVIG) proved most effective, inducing coordinated cellular and molecular responses, reversing age-related immune decline, and modulating proteins linked to chronic inflammation. Integrative analysis identified baseline biomarkers predictive of positive outcomes, suggesting TPE-IVIG is particularly beneficial for individuals with poorer initial health status. This is the first multi-omics study to examine various TPE modalities to slow epigenetic biologic clocks, which demonstrate biological age rejuvenation and the molecular features associated with this rejuvenation. Trial Registration: Registered trial NCT06534450 on clinicaltrials.gov under the purview of the Diagnostic Investigational Review Board.

Keywords:  aging; anti‐aging; human; inflammation

DOI:  https://doi.org/10.1111/acel.70103
Nat Aging. 2025 May 28.

The geroprotectors trametinib and rapamycin combine additively to extend mouse healthspan and lifespan.

Lisonia Gkioni, Tobias Nespital, Maarouf Baghdadi, Carolina Monzó, Jitin Bali, Taim Nassr, Anna Lena Cremer, Andreas Beyer, Joris Deelen, Heiko Backes, Sebastian Grönke, Linda Partridge.

Suppression of the insulin-IGF-mTORC1-Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras-MEK-ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans.

DOI: https://doi.org/10.1038/s43587-025-00876-4
Stem Cell Res Ther. 2025 May 28. 16(1): 263

Extracellular vesicles in age-related diseases: disease pathogenesis, intervention, and biomarker.

Puan Haliza Lintang Putri, Samira Husen Alamudi, Xuan Dong, Ying Fu.

  Aging is a multifactorial biological process characterized by the irreversible accumulation of molecular damage, leading to an increased risk of age-related diseases. With the global prominent rise in aging populations, elucidating the mechanisms underlying the aging process and developing strategies to combat age-related diseases have become a pressing priority. Extracellular vesicles (EVs) have gained significant attention due to their role in intercellular communication. EVs are known for their ability to deliver biocargoes, such as miRNA, proteins, and lipids, implicating their involvement in disease pathogenesis and intervention. In this review article, we explore the dual role of EVs in age-related diseases: contributing to the pathogenesis of diseases by transferring deleterious molecules, while also offering therapeutic ability by transferring beneficial molecules. We also highlight the application of EVs as biomarkers for early diagnosis of age-related diseases, paving the way for early intervention and precision medicine. Additionally, we discuss how analysing the composition of EVs cargo can provide insights into disease progression. Finally, we address the challenges and future perspectives of EV-based-therapy in clinical translation, including standardization of EVs isolation methods and improving cargo specificity.

Keywords:  Age-related disease; Biomarker; Extracellular vesicles; Pathogenesis; Therapy

DOI:  https://doi.org/10.1186/s13287-025-04374-7
Adv Sci (Weinh). 2025 May 28. e2417728

Nucleotides as an Anti-Aging Supplementation in Older Adults: A Randomized Controlled Trial (TALENTs study).

Shuyue Wang, Lixia Song, Rui Fan, Qianqian Chen, Ruisheng Fu, Mei You, Yuxiao Wu, Meng Cai, Yong Li, Meihong Xu.

  Aging impairs nutrient metabolism and accelerates biological aging, negatively affecting health and longevity. The Targeting Aging and Longevity with Exogenous Nucleotides (TALENTs) trial (ClinicalTrials.gov: NCT05243108) aimed to explore whether nucleotides (NTs) supplementation can delay biological aging and improve health outcomes in the elderly. The trial is a 19-week, double-blind, randomized, placebo-controlled study in Chengdu, China, with 121 participants (60-70 years). Participants are randomly assigned to either NTs (1.2 g day-1) or placebo group (1:1). The results of primary outcomes showed that NTs had significantly greater reduction in median DNA methylation age compared to placebo over 19 weeks (β = -3.08 years, 95% CI: -5.07 to -1.10, P = 0.0023), with a trend toward reduction observed over 11 weeks (β = -1.94 years, 95% CI: -4.32 to 0.45, P = 0.11); whereas no significant difference changes of leukocyte telomere length are showed between groups (week 11: β = 0.09, 95% CI: -0.10 to 0.29, P = 0.36; week 19: β = 0.12, 95% CI: -0.05 to 0.28, P = 0.18). Insulin sensitivity improved in the NTs group, with a significant reduction in HOMA-IR over 19 weeks (β = -0.45, 95% CI: -0.86 to -0.04, P = 0.033). No severe adverse events or significant changes in safety indicators are reported. Together, our findings establish that NTs may delay biological aging and improve insulin sensitivity with a well-tolerated safety profile.

Keywords:  DNA methylation age; anti‐aging intervention; body composition; insulin sensitivity; nucleotides supplementation

DOI:  https://doi.org/10.1002/advs.202417728
Aging Cell. 2025 May 28. e70119

Circadian Gene BMAL1 Regulation of Cellular Senescence in Thyroid Aging.

Dandan Zong, Baihui Sun, Qiting Ye, Hongxin Cao, Haixia Guan.

  As global aging accelerates, the incidence of thyroid diseases, particularly hypothyroidism, is rising in the elderly. The thyroid-stimulating hormone (TSH) levels increase in healthy elderly populations. However, whether the thyroid undergoes cellular senescence and how this relates to thyroid hormone (TH) synthesis remain unclear. To investigate the molecular and functional characteristics of thyroid aging, we performed scRNA-seq on human thyroids from young, middle-aged, and old groups, identifying thousands of aging-related differentially expressed genes and revealing the early onset of aging in the middle-aged group. As aging progresses, the expression levels of genes related to TH synthesis increase, suggesting that epithelial cells (EPI) adjust their gene expression in response to elevated TSH levels. Additionally, the senescence-associated secretory phenotype (SASP) in EPI cells is progressively enhanced with aging. We identified a subgroup of epithelial cells (CDKN1A_EPI) characterized by reduced functionality and significantly elevated levels of cellular senescence. We found that the core circadian rhythm gene BMAL1 (ARNTL) is downregulated during aging. We further validated this finding using the thyroid-specific Bmal1 knockout mouse model, showing that the downregulation of Bmal1 inhibits the expression of Nfkbia (NF-κB inhibitor alpha), thereby accelerating cellular senescence and impairing hormone synthesis. Finally, through cell line experiments and transcriptome sequencing, we confirmed that BMAL1 knockout leads to decreased NFKBIA expression, promoting thyroid cellular senescence. Our study demonstrates that circadian rhythm disruption accelerates cellular senescence in the thyroid and exacerbates the decline of thyroid function, providing a novel theoretical foundation for understanding thyroid aging mechanisms and maintaining thyroid function stability.

Keywords:  BMAL1; cellular senescence; rhythm; thyroid aging

DOI:  https://doi.org/10.1111/acel.70119
Z Naturforsch C J Biosci. 2025 May 23.

From current landscape to future horizon in stem cell therapy for tissue regeneration and wound healing: bridging the gap.

Kashvy R Morakhia, Aayushi C Shah, Mannat P Patel, Jainam K Shah, Rajanikant Patel, Mehul R Chorawala.

  Stem cell therapy has emerged as a groundbreaking approach in regenerative medicine, offering immense potential for tissue regeneration and wound healing. Stem cells, with their ability to self-renew and differentiate into specialized cell types, provide innovative therapeutic strategies for variety of medical conditions. Key stem cell types, including embryonic, induced pluripotent, and adult stem cells such as mesenchymal and hematopoietic stem cells, play pivotal roles in regenerative processes and wound repair. In tissue regeneration, stem cells replenish damaged or necrotic cells by differentiating into specialized cell types like bone, muscle, or nerve cells, thus restoring the structural and functional integrity of tissues. In wound healing, stem cells stimulate angiogenesis, generate new skin cells, and modulate immune responses to enhance repair. This multifaceted therapeutic potential has paved the way for clinical applications in cardiovascular, neurological, musculoskeletal, and autoimmune disorders, as well as skin and burn injuries. This review highlights recent advancements in stem cell therapy, exploring its clinical applications and addressing challenges such as immune rejection, ethical concerns, scalability, and the need for long-term clinical trials. The article underscores the importance of continued research to fully realize the transformative potential of stem cell therapy in modern medicine.

Keywords:  cellular therapy; regenerative medicine; stem cells; tissue regeneration; wound healing

DOI:  https://doi.org/10.1515/znc-2025-0020
Mol Biol Rep. 2025 May 30. 52(1): 521

Unraveling senescence in cancer: mechanistic complexities and therapeutic opportunities.

Prajakta Tiwari, Shreesh Kumar Shukla, Smita Rastogi Verma.

  Senescence is a pivotal cellular process, which also plays a major role in development, immune regulation, tissue repair, and aging, triggered by stressors such as telomere shortening, oncogene activation, and DNA damage. Characterized by distinct morphological and molecular features, senescence is known to act as a tumor suppressive mechanism through irreversible cell cycle arrest. However, emerging studies reveal a paradox: prolonged senescence in cancer cells can drive tumorigenesis via the senescence-associated secretory phenotype, promoting proliferation, invasion, and metastasis. This comprehensive review elucidates the molecular intricacies of senescence to induce growth arrest, enhance immune surveillance, and favorably modulate the tumor microenvironment to inhibit cancer progression. Additionally, it examines the senescence-inducing effects of conventional therapies and explores the potential of emerging therapies, including targeted therapies and chimeric antigen receptor T cell therapy. The present review also highlights the promise of senotherapeutic strategies in selectively targeting senescent cells to improve therapeutic outcomes. It discusses the innovative integration of machine learning tools for biomarker discovery and patient stratification offering a transformative approach to improve cancer treatment efficacy.

Keywords:  Machine learning; Senescence; Senescence associated secretory phenotype; Senescence-targeted cancer therapy; Senocidals; Senotherapy

DOI:  https://doi.org/10.1007/s11033-025-10630-z
Free Radic Biol Med. 2025 May 23. pii: S0891-5849(25)00699-9. [Epub ahead of print]

Cationic microbubbles loading shFOXO4/SDF1 rejuvenate the aged heart and alleviate myocardial ischemia-reperfusion injury in the elderly.

Xingpei Jiang, Limeng Chao, Kexun Liu, Yuanzhong Zhao, Jie Wu, Chang Liu, Wei Chen, Dongyang Zhang, Hai Tian.

  Aging is a significant risk factor for cardiovascular diseases, with ischemic heart disease (IHD) being the leading cause of cardiovascular-related mortality. Inhibition of FOXO4, which selectively eliminates senescent cells, offers protective effects on the aging myocardium. However, the removal of senescent cells may lead to a reduction in tissue cell density, thereby exacerbating tissue space formation and perivascular fibrosis. Therefore, selectively eliminating senescent cells in the aging heart, while simultaneously replenishing therapeutic bone marrow-derived mesenchymal stem cells (BMSCs), holds substantial therapeutic potential for synergistically combating cardiac aging. This study proposes a promising cardiac rejuvenation strategy using ultrasound-targeted microbubble destruction (UTMD)-mediated delivery of shFOXO4/SDF1 to eliminate cellular senescence and enhance BMSC homing. Transcriptomic analysis identified FOXO4 as a pivotal transcription factor in cardiac aging, with FOXO4 protein predominantly expressed in cardiac fibroblasts (CFs) and vascular endothelial cells in the myocardium of aged rats. Knockdown of FOXO4 in aging CFs reversed cellular senescence, and co-culturing these rejuvenated CFs with BMSCs further enhanced the reversal of senescence and bolstered resistance to oxidative stress. The use of UTMD for delivering shFOXO4/SDF1 in dual-gene therapy significantly enhanced BMSC homing, ameliorating cardiac aging, oxidative stress, and inflammation. In an ischemia-reperfusion injury (MIRI) model, pretreatment with shFOXO4/SDF1 effectively reduced cardiomyocyte apoptosis, promoted neovascularization, reduced infarct size, and improved cardiac function. The combined removal of senescent cells and enhanced BMSC homing synergistically ameliorated cardiac aging and improved post-MIRI prognosis in aging hearts. These findings provide novel insights and potential therapeutic strategies for addressing cardiac aging and age-related heart diseases.

Keywords:  Aging; Gene therapy; Myocardial ischemia-reperfusion injury; Ultrasound targeted microbubble destruction

DOI:  https://doi.org/10.1016/j.freeradbiomed.2025.05.416
Redox Biol. 2025 May 21. pii: S2213-2317(25)00208-3. [Epub ahead of print]84 103695

IDO1 improves postischemic neovascularization in aged mice by boosting endothelial NAD+ de novo synthesis and curbing endothelial senescence.

Minghong Chen, Junyu Chen, Yu Liu, Jing Chen, Meilian Yao, Xuerui Wang, Jian Zhang, Miao Pan, Jipeng Zhou, Yongping Bai.

   INTRODUCTION: Peripheral arterial disease (PAD) is prevalent among the elderly, and therapeutic neovascularization is a research hotspot in PAD treatment. Supplementing nicotinamide adenine dinucleotide (NAD+) precursors is an important approach for promoting neovascularization, but clinical trials in the elderly PAD patients have shown limited success. This study aims to find effective ways to boost NAD+ levels in elderly PAD patients to enhance neovascularization.
METHODS: Transcriptome and NAD+-targeted metabolomics analyses were conducted on ischemic hindlimb muscle endothelial cells (ECs). The role of indoleamine 2,3-dioxygenase 1 (IDO1) in postischemic neovascularization was studied using global knockout mice. Mechanisms regulating IDO1 expression were investigated through transcriptomics and functional experiments. The effects of IDO1 protein on postischemic neovascularization were evaluated in vivo and in vitro. Plasma IDO1 levels were measured in young and elderly PAD patients and correlated with clinical indicators of PAD.
RESULTS: In aged mice, ECs exhibited decreased NAD+ de novo synthesis and IDO1 transcription. IDO1 deficiency induced the decline of ECs NAD+ de novo synthesis and ECs senescence, impaired neovascularization in young mice. Elevated IL-17A/F inhibited IDO1 transactivation via CREB, impairing neovascularization. IDO1 administration alleviated the decline of ECs NAD+ de novo synthesis and ECs senescence, and enhanced neovascularization in aged mice. Plasma IDO1 levels were lower in elderly PAD patients, correlating positively with disease severity, onset risk, and cardiovascular outcomes.
CONCLUSION: ECs NAD+ metabolism imbalance is driven by decreased de novo synthesis of NAD+ and targeting IDO1 to elevate NAD+ levels could be a potential therapeutic direction for elderly PAD patients.

Keywords:  Aging; Cellular senescence; Indoleamine 2,3-dioxygenase 1; Neovascularization; Nicotinamide adenine dinucleotide; Peripheral artery disease

DOI:  https://doi.org/10.1016/j.redox.2025.103695