Aisha Siddique, Ismail M Shakir, Mo Li
· Cell regeneration (London, England)
· Bioscience Program, Biological and Environmental Science and Engineering Division (BESE), King Abdullah University of Science and Technology (KAUST), Thuwal, 23955, Saudi Arabia.
· pubmed
Aging is characterized by progressive functional decline driven by stem cell exhaustion, chronic inflammation, and cellular senescence. Mesenchymal progenitor cells (MPCs), which play a central role in tissue repair, are particularly vulnerable to age-associated dysfunction. Lei ...
Aging is characterized by progressive functional decline driven by stem cell exhaustion, chronic inflammation, and cellular senescence. Mesenchymal progenitor cells (MPCs), which play a central role in tissue repair, are particularly vulnerable to age-associated dysfunction. Lei et al. (Cell 188:1-22, 2025) address this limitation by engineering human embryonic stem cell-derived MPCs with enhanced FOXO3 activity (termed SRCs). Intravenous administration of FOXO3-SRCs to aged cynomolgus macaques significantly slowed aging across multiple organs compared to wild-type MPCs. SRC treatment improved cognitive performance, preserved brain structure, protected bone integrity, and rejuvenated immune function. Transcriptomic and DNA methylation aging clocks revealed substantial reductions in biological age, with the most pronounced rejuvenation observed in the reproductive system, skin, lung, muscle, and hippocampus. These effects were partly attributed to SRC-derived exosomes enriched in gero-protective proteins and metabolites. Importantly, SRCs exhibited robust safety, showing no tumorigenicity or immunogenicity. This work positions FOXO3-enhanced MPCs and their exosomes as promising candidates for systemic anti-aging interventions, shifting the therapeutic paradigm from treating individual diseases to targeting the aging process itself.
Longevity Relevance Analysis
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The paper claims that systemic infusion of FOXO3-enhanced mesenchymal progenitor cells can significantly slow aging and rejuvenate multiple organ systems in aged primates. This research addresses the root causes of aging by targeting cellular senescence and stem cell dysfunction, making it relevant to longevity research.
Terytty Yang Li, Arwen W Gao, Rendan Yang ...
· Nature cell biology
· State Key Laboratory of Genetics and Development of Complex Phenotypes, Shanghai Key Laboratory of Metabolic Remodeling and Health, Laboratory of Longevity and Metabolic Adaptations, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, China. [email protected].
· pubmed
Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific...
Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H
Longevity Relevance Analysis
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The paper claims that silencing specific vacuolar H+ ATPase can enhance lysosomal activity to counteract aging-related decline. This research is relevant as it addresses mechanisms that could potentially extend healthspan by targeting cellular processes linked to aging.
Avnish Kumar Verma, Sandeep Singh, Syed Ibrahim Rizvi
· Longevity
· Department of Biochemistry, University of Allahabad, Allahabad, 211002, India.
· pubmed
The circadian clocks of the cell orchestrate a daily transcriptional rhythm that schedules key activities of the cell to maintain homeostasis and support resilience. Circadian rhythm is driven by the periodic oscillations of transcriptional activators and translational repressors...
The circadian clocks of the cell orchestrate a daily transcriptional rhythm that schedules key activities of the cell to maintain homeostasis and support resilience. Circadian rhythm is driven by the periodic oscillations of transcriptional activators and translational repressors, occurring in both the central and peripheral clocks. Accumulating evidence shows that aging impairs the functional synchrony of the circadian system which further escalate age-related disorders. In addition, the technological aspects of modern society, including constant work schedules and extensive use of personal electronics, have led to a significant rise in circadian disorders. Circadian dysfunction seems to adversely impact aging and longevity in animal models. Therefore, it is essential to conduct comprehensive studies to identify factors that worsen with aging and to discover therapeutic options for promoting healthy aging. This review examines how aging affects circadian function and the reciprocal effects of circadian disruption (CD) on aging and longevity. Further, we highlight the recent findings on non-pharmacological aspects such as dietary restrictions and physical exercise as a regulator of circadian rhythms, aging attenuation, and extending lifespan in mammals. Thus, resetting the circadian clock may lead to better synchrony in cellular homeodynamics and physiology which offers healthy aging and increased life span.
Longevity Relevance Analysis
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The paper claims that resetting the circadian clock can improve cellular homeodynamics and promote healthy aging and increased lifespan. This research is relevant as it explores the relationship between circadian rhythms and aging, addressing potential root causes of aging and longevity rather than merely focusing on age-related diseases.
Dey, A. K., Olinger, B., Boroumand, M. ...
· biochemistry
· National Institute on Aging
· biorxiv
Assessing and validating circulating biomarkers is essential for the development of pre-clinical biomarkers that predict biological aging and aging-phenotypes in mice. However, comprehensive proteomics of serum, especially in longitudinal mouse studies, is limited by low volumes ...
Assessing and validating circulating biomarkers is essential for the development of pre-clinical biomarkers that predict biological aging and aging-phenotypes in mice. However, comprehensive proteomics of serum, especially in longitudinal mouse studies, is limited by low volumes of samples. In this study, we develop a workflow for comprehensive and quantitative proteomic analysis of low volume mouse serum and demonstrate its utility and performance in identifying and evaluating key associations with aging phenotypes. Notably, a nanoparticle (NP)-based serum processing workflow coupled to mass spectrometry (MS) increases proteomic coverage by 2 to 4-fold across a range of volumes and provides a quantitative and reproducible (CV < 10%) pipeline for NP-based studies. In a study of 30 mice (aged 12, 24, and 30 months), we uncovered 3992 protein groups across all samples (2235 on average) in 20uL of serum and highlight novel insights into aging-associated changes in serum and associations with glucose and body composition. With 1uL additional serum, a 48-cytokine assay quantified 39 additional proteins not identified by MS. This study establishes a powerful workflow that enables deep quantitative proteomics of biologically relevant proteins in volumes feasibly obtained from mice (20 uL of serum) and presents fundamental insights into the aging serum proteome.
Longevity Relevance Analysis
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The study presents a novel workflow for quantitative proteomic analysis of low volume mouse serum, revealing insights into aging-associated changes in serum proteins. This research is relevant as it aims to identify biomarkers that could help in understanding biological aging and its phenotypes, which is crucial for addressing the root causes of aging.
Christoph Benner, Matteo Cesari, Ritu Sadana
· Aging cell
· Ageing and Health Unit, Department of Maternal, Newborn, Child, and Adolescent Health and Ageing, World Health Organization, Geneva, Switzerland.
· pubmed
The World Health Organization (WHO) defines healthy ageing as the process of developing and maintaining functional ability, comprising an individual's intrinsic capacity, the environment and the interaction of the two. The framework is based on a positive approach to ageing, givi...
The World Health Organization (WHO) defines healthy ageing as the process of developing and maintaining functional ability, comprising an individual's intrinsic capacity, the environment and the interaction of the two. The framework is based on a positive approach to ageing, giving value to the resources individuals can rely upon as they age and that they can build their physical, mental and social health, and overall well-being. To promote healthy ageing, it is important to understand better the biological mechanisms underlying this phenomenon from this positive perspective. Our knowledge about cellular processes that drive human ageing has increased dramatically, with current evidence identifying 12 hallmarks of ageing. Dysbiosis is one of these and is broadly defined as a 'deranged microbiological composition in and on the human body'. It is often measured by quantitatively and qualitatively evaluating the bacterial species in the gut. A major feature of dysbiosis and other markers of ageing is that these focus on age-related impairments, contributing to the onset of adverse outcomes over time rather than highlighting features that promote healthy ageing. Scientific literature addressing the hallmarks of healthy ageing, including those potentially positively affecting intrinsic capacity, is lacking. To this end, we propose the concept of gut eubiosis, the homeostatic state of commensal gut bacteria and their metabolites, as proof of concept, serving as a hallmark of healthy ageing. Importantly, this work adopts a life course approach to explore how a person's intrinsic capacities evolve with gut microbiota modifications at different life stages.
Longevity Relevance Analysis
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The paper proposes that gut eubiosis serves as a hallmark of healthy ageing, emphasizing the importance of microbiota in promoting intrinsic capacity throughout the life course. This research is relevant as it explores biological mechanisms underlying healthy ageing, focusing on the role of gut microbiota in enhancing functional ability and overall well-being, rather than merely addressing age-related diseases.
Ekaterina Proshkina, Natalya Pakshina, Lyubov Koval ...
· Drosophila melanogaster
· Institute of Biology, Komi Science Centre, Ural Branch, Russian Academy of Sciences, Syktyvkar, Russian Federation, 167982. [email protected].
· pubmed
Small non-coding RNAs coordinate essential cellular processes, including gene expression regulation, genome stability maintenance, and transposon suppression. These processes determine aging, lifespan, and resistance of cells and organisms to stress. In this work, we conducted a ...
Small non-coding RNAs coordinate essential cellular processes, including gene expression regulation, genome stability maintenance, and transposon suppression. These processes determine aging, lifespan, and resistance of cells and organisms to stress. In this work, we conducted a comprehensive study of the geroprotective effects of overexpression of two Dicer family genes (Dcr-1 and Dcr-2, which are responsible for the biogenesis of miRNAs and siRNAs) in different tissues of Drosophila melanogaster (nervous system, fat body, intestine, muscles). Activation of the Dicer genes affected the lifespan in a tissue- and sex-depending manner. Females with Dcr-1 overexpression in the nervous system exhibited a significant and reproducible increase in both median (10.0-13.4%, p < 0.001) and maximum lifespan (10.0-13.4%, p < 0.01). However, in other cases, the effect was insignificant or negative. Additionally, flies with neuronal Dcr-1 activation had increased expression of several longevity genes (Sirt1, bsk, tgo, Gadd45, Xpc, Azot, foxo, Hsf, Tsc1) and significantly increased survival after acute exposure to 700 Gy γ-radiation (40-200%, p < 0.05). But they had reduced resistance to starvation. This indicates a crucial role of the miRNA machinery and the Dicer family in providing protection against genotoxic effects and coordinating metabolic processes.
Longevity Relevance Analysis
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Overexpression of Dicer family genes in Drosophila can influence lifespan and stress resistance in a tissue- and sex-specific manner. This study explores the role of small non-coding RNAs in aging and lifespan extension, addressing fundamental mechanisms of longevity rather than merely treating age-related symptoms.
Moses, E., Franek, R., Atlan, T. ...
· genetics
·
· biorxiv
The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly in the context of ecologically relevant life histories. Here, we identify ...
The antagonistic pleiotropy theory of aging predicts genetic trade-offs between early-life and late-life fitness. However, empirical evidence for such trade-offs in vertebrates remains scarce, particularly in the context of ecologically relevant life histories. Here, we identify vestigial-like 3 (vgll3), a transcription cofactor previously linked to age at maturity in humans and male Atlantic salmon through GWAS, as an antagonistically pleiotropic gene in the turquoise killifish (Nothobranchius furzeri). Selective disruption of vgll3 isoforms accelerates male growth and maturation in an isoform- and dose-dependent manner. Transcriptomic analysis, supported by cellular and physiological phenotypes, indicated increased cell proliferation and elevated germline production. However, early-life maturation incurs a late-life cost, linked to altered DNA damage response. Older mutant males develop melanoma-like tumors, validated via transplantation into immunodeficient rag2 models, and exhibit elevated age-related mortality rate. These findings highlight vgll3 as a key regulator of vertebrate life-history trade-offs, balancing early-life fitness with late-life disease risks.
Longevity Relevance Analysis
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The paper claims that the vgll3 gene regulates trade-offs between early-life fitness and late-life disease risks in vertebrates. This research is relevant as it explores genetic mechanisms that influence aging and longevity, specifically addressing the antagonistic pleiotropy theory and its implications for life-history trade-offs.
Li, X., Li, W., Gao, A. W. ...
· genetics
· Laboratory of Integrative Systems Physiology, Ecole Polytechnique Federale de Lausanne
· biorxiv
The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role i...
The mitochondrial unfolded protein response (UPRmt) is one of the mito-nuclear regulatory circuits that restores mitochondrial function upon stress conditions, promoting metabolic health and longevity. However, the complex gene interactions that govern this pathway and its role in aging and healthspan remain to be fully elucidated. Here, we activated the UPRmt using doxycycline (Dox) in a genetically diverse C. elegans population comprising 85 strains and observed large variation in Dox-induced lifespan extension across these strains. Through multi-omic data integration, we identified an aging-related molecular signature that was partially reversed by Dox. To identify the mechanisms underlying Dox-induced lifespan extension, we applied quantitative trait locus (QTL) mapping analyses and found one UPRmt modulator, fipp-1/FIP1L1, which was functionally validated in C. elegans and humans. In the human UK Biobank, FIP1L1 was associated with metabolic homeostasis, underscoring its translational relevance. Overall, our findings demonstrate a novel UPRmt modulator across species and provide insights into potential translational research.
Longevity Relevance Analysis
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The paper identifies a UPRmt modulator, fipp-1/FIP1L1, that influences lifespan extension in C. elegans and has translational relevance in humans. The research explores mechanisms of aging and potential interventions that could impact longevity.
Zhao Cui, Jiameng Li, Caifeng Li ...
· Cell reports
· Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing 100700, China; Laboratory of Cardiovascular Diseases, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing 100091, China.
· pubmed
α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, acc...
α-ketoglutaric acid (AKG), a tricarboxylic acid cycle metabolite central to aerobic metabolism and longevity, retains unresolved anti-aging protein targets. Here, we demonstrate that reduced isocitrate dehydrogenase 1 (IDH1) expression during senescence lowers AKG production, accelerating the aging of mesenchymal stem cells (MSCs). Exogenous AKG or IDH1 overexpression restores AKG levels, enabling 2-oxoglutarate and Fe(II)-dependent oxygenase domain-containing protein 1 (OGFOD1)-catalyzed hydroxylation of ribosomal protein S23 (RPS23) at proline 62. Mechanistically, AKG stabilizes the OGFOD1-RPS23 complex, enhancing translation accuracy to limit misfolded protein accumulation while sustaining synthesis rates, thereby balancing proteostasis. The natural flavonoid scutellarin (Scu), identified as an IDH1 agonist, elevates AKG to delay MSC senescence. In aged mice, Scu improves cognitive function, reduces osteoporosis and skin aging, and suppresses senescence-associated secretory phenotype. Our findings identify the AKG-IDH1-RPS23 axis as a regulator of stem cell senescence and we propose metabolic reprogramming strategies for anti-aging therapies.
Longevity Relevance Analysis
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The paper claims that α-ketoglutaric acid (AKG) and its modulation through IDH1 can delay mesenchymal stem cell senescence. This research addresses mechanisms underlying cellular aging and proposes metabolic interventions, which are central to longevity studies.
James P Garrahy
· Journal of Alzheimer's disease : JAD
· Independent Researcher.
· pubmed
Late-onset Alzheimer's disease (LOAD) is traditionally attributed to amyloid-β (Aβ) accumulation and tau pathology as primary drivers of neurodegeneration. However, growing evidence suggests these may be secondary events arising from earlier disturbances in brain metabolism and l...
Late-onset Alzheimer's disease (LOAD) is traditionally attributed to amyloid-β (Aβ) accumulation and tau pathology as primary drivers of neurodegeneration. However, growing evidence suggests these may be secondary events arising from earlier disturbances in brain metabolism and lipid homeostasis. The ε4 allele of apolipoprotein E (ApoE4) remains the strongest genetic risk factor for LOAD, with carriers exhibiting both increased lifetime risk and earlier age of onset compared to ε2 or ε3 carriers. ApoE4 disrupts lipid metabolism and is associated with increased lipid droplet accumulation within astrocytes, implicating astrocytic lipidopathy in disease pathogenesis. Here, we propose a self-reinforcing pathogenic feedback loop-driven by dysregulated lipid homeostasis, chronic neuroinflammation, impaired glucose-handling, and cerebrovascular dysfunction-that culminates in astrocytic bioenergetic failure. This framework helps explain why ApoE4 carriers reach a critical bioenergetic threshold earlier in life, triggering the clinical onset of LOAD. Targeting astrocytic lipid homeostasis, through interventions such as blood-brain barrier-permeable statins, choline supplementation, or metabolic therapies, may offer novel strategies to delay disease progression or onset. Beyond AD, the framework proposed here, if validated, may have broader implications for unifying the cellular origins of age-related degenerative diseases and cancer through a shared vulnerability to progressive bioenergetic collapse.
Longevity Relevance Analysis
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The paper proposes that dysregulated lipid homeostasis and bioenergetic failure in astrocytes contribute to the pathogenesis of late-onset Alzheimer's disease in ApoE4 carriers. This research is relevant as it addresses underlying metabolic disturbances that may be linked to aging and offers potential strategies for delaying disease onset, aligning with longevity research goals.
Claudia Lennicke, Ivana Bjedov, Sebastian Grönke ...
· Autophagy
· MRC Laboratory of Medical Sciences (LMS), London, UK.
· pubmed
Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H
Dysregulation of redox homeostasis is implicated in the ageing process and the pathology of age-related diseases. To study redox signalling by H
Longevity Relevance Analysis
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Enhancing autophagy through redox regulation can extend lifespan in Drosophila. This research addresses the underlying mechanisms of aging by exploring how redox homeostasis and autophagy influence lifespan, which is directly relevant to longevity studies.
Divya Ganapathi Sankaran, Hongya Zhu, Viviana I Maymi ...
· Cell reports
· Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
· pubmed
T cell development is fundamental to immune system establishment, but how this development changes with age remains poorly understood. Here, we construct a transcriptional and chromatin accessibility atlas of T cell developmental programs in neonatal and adult mice, revealing the...
T cell development is fundamental to immune system establishment, but how this development changes with age remains poorly understood. Here, we construct a transcriptional and chromatin accessibility atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene-regulatory programs and their link to age-related differences. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern the effector response and cell cycle. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing readout, to uncover a conserved transcriptional regulator, Zbtb20, that contributes to age-dependent differences in T cell development. In summary, our study defines gene-regulatory programs that regulate age-specific differences in T cell development.
Longevity Relevance Analysis
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The study identifies age-related differences in T cell development and gene-regulatory programs. This research is relevant as it explores the underlying mechanisms of immune system changes with age, which could contribute to understanding the aging process and potential interventions.
Xie, H., You, Z., Liao, B. ...
· bioinformatics
· The Affiliated Hospital of Southwest Medical University
· biorxiv
Background: Chronic heart failure (CHF), the terminal phase of cardiovascular disease progression, has emerged as an increasingly severe global public health concern. Despite current therapeutic approaches aimed at symptom relief, their long-term effectiveness remains limited, ur...
Background: Chronic heart failure (CHF), the terminal phase of cardiovascular disease progression, has emerged as an increasingly severe global public health concern. Despite current therapeutic approaches aimed at symptom relief, their long-term effectiveness remains limited, urgently necessitating the exploration of novel treatment strategies. This study endeavored to explore the role of cellular senescence in CHF, identify the characteristic genes linked to cellular senescence, and predict potential therapeutic agents. Methods: We acquired CHF-related datasets from the Gene Expression Omnibus database and cell senescence-related genes from the CellAge database to identify differentially expressed cell senescence-related genes. We then conducted Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses to elucidate the functions of these differentially expressed genes, constructed a protein-protein interaction network, and screened hub genes. Using receiver operating curve (ROC) analysis, we developed a diagnostic model based on these hub genes. Furthermore, we constructed networks for the hub genes involving miRNAs, lncRNAs, transcription factors, and drugs. Subsequently, we explored the potential mechanism of action of metformin in the treatment of CHF through molecular docking studies. Lastly, we verified the expression of the hub genes in a doxorubicin-induced CHF model in rats. Results: We ultimately identified nine hub genes associated with cellular senescence: STAT1, MMP9, MAP2K1, SOCS1, SDC1, MET, EIF4EBP1, ATF3, and NAMPT. These genes exhibited significant differential expression between CHF and normal tissues. The constructed diagnostic model demonstrated robust diagnostic performance in ROC curve analysis, with an area under the curve exceeding 0.7, thereby providing biomarker support for early CHF diagnosis. Furthermore, we identified a regulatory network comprising 94 lncRNAs, 63 miRNAs, and 11 transcription factors and screened 42 potential therapeutic drugs. Subsequent molecular docking simulations revealed that metformin could effectively bind to the hub genes. Finally, we validated the expression of some hub genes in a rodent CHF model, in which gene expression regulation varied across diverse experimental settings. Conclusions: Our research identified nine genes cellular senescence-related genes with potential roles in CHF pathogenesis, offering fresh perspectives concerning the diagnosis and treatment of CHF.
Longevity Relevance Analysis
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The paper identifies nine hub genes associated with cellular senescence that may play a role in chronic heart failure pathogenesis. The focus on cellular senescence as a mechanism underlying chronic heart failure connects to broader themes in longevity research, as it addresses potential root causes of age-related diseases rather than merely treating symptoms.
Yuichiro Nakata, Takeshi Ueda, Yasuyuki Sera ...
· EMBO reports
· Department of Systems Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan. [email protected].
· pubmed
Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their func...
Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their function is largely unknown. Here, we show that JMJD3, a histone demethylase, activates cellular senescence by upregulating p16
Longevity Relevance Analysis
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JMJD3 activates cellular senescence in hematopoietic stem and progenitor cells by upregulating p16. This research addresses the mechanisms of cellular senescence, which is a fundamental aspect of aging and its impact on regenerative capacity, thus contributing to the understanding of aging processes.
Majeed, Y., Halabi, N. M., Engelke, R. ...
· physiology
· Weill Cornell Medicine in Qatar
· biorxiv
Sirtuins are NAD+-dependent histone deacetylases that play a key role in metabolism. Sirtuin activity is compromised in aging and metabolic disorders, and pharmacological strategies that promote sirtuin function including NAD+ boosting approaches show potential as therapeutics. T...
Sirtuins are NAD+-dependent histone deacetylases that play a key role in metabolism. Sirtuin activity is compromised in aging and metabolic disorders, and pharmacological strategies that promote sirtuin function including NAD+ boosting approaches show potential as therapeutics. To study the impact of nicotinamide mononucleotide (NMN) supplementation in mice in high fat diet (HFD) induced obesity and the role of SIRT1, a sirtuin family member, in mediating the NMN response, we administered NMN to mice in drinking water to boost NAD+ in control and in inducible SIRT1 knock-out mouse models and performed a combination of metabolic phenotyping, lipid profiling and plasma proteomics in these mice. We discovered that supplementation with NMN mitigated diet induced weight gain by enhancing energy expenditure, corrected dyslipidemia, and reversed perturbations in fasting blood glucose, all in a SIRT1-dependent manner. On the other hand, NMN-induced reductions in fat mass, fluid mass, eWAT and mesenteric WAT were SIRT1 independent. Proteomic approaches in plasma samples using O-Link and mass-spectrometry provided novel insights into key obesity- and NMN-dependent changes in circulating molecules with potential relevance to inflammation, liver function, and dyslipidemia. We discovered SIRT1 dependent and independent alterations in key circulating plasma proteins and identified key metabolic and molecular pathways that were significantly affected by HFD, several of which were reverted by oral NMN administration. Glucose metabolism, cholesterol metabolism and immune-related pathways are among the most significantly affected changes. Causal analysis of proteomic data suggests that observed effects could be mediated by transcription regulators FBXW7, ADIPOR2 and PRDM16. Collectively, our data support the hypothesis that promoting SIRT1 function by boosting NAD+ levels in vivo may be a useful strategy to mitigate obesity and associated cardiovascular complications such as dyslipidemia.
Longevity Relevance Analysis
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Oral nicotinamide mononucleotide (NMN) supplementation mitigates diet-induced obesity and dyslipidemia through SIRT1-dependent and independent mechanisms. The paper addresses the role of NAD+ and sirtuins in metabolism, which are critical factors in aging and age-related metabolic disorders, thus contributing to the understanding of potential interventions for longevity.
Qin He, Shupan Guo, Aolan Zhou ...
· GeroScience
· Department of Pulmonary and Critical Care Medicine, Respiratory Infection and Intervention Laboratory of Frontiers Science Center for Disease-Related Molecular Network, and State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
· pubmed
Aging and age-related disorders are significant global health concerns, driving interest in potential preventative strategies. In this study, we established a high-throughput screening system to reveal the effects of quinacrine and rimonabant on lifespan extension in C. elegans. ...
Aging and age-related disorders are significant global health concerns, driving interest in potential preventative strategies. In this study, we established a high-throughput screening system to reveal the effects of quinacrine and rimonabant on lifespan extension in C. elegans. Mechanistically, quinacrine influences the metabolic and immune pathways through the insulin/insulin-like growth factor (IIS) pathway, as it fails to prolong longevity in IIS pathway mutants while boosting the expression of the downstream gene sod-3. Metabolomic profiling revealed a significant elevation of phosphatidylserine in quinacrine-treated worms. Parallel investigations showed that rimonabant exerts its lifespan-extending effects via the IIS pathway, specifically through the DAF-2/HSF-1 regulatory axis. It promotes longevity of C. elegans by enhancing antioxidant defense and detoxification pathways. Our findings position both quinacrine and rimonabant as promising anti-aging candidates, offering novel mechanistic insights for developing interventions against age-related disorders.
Longevity Relevance Analysis
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Quinacrine and rimonabant extend lifespan in C. elegans through modulation of the insulin/insulin-like growth factor pathway. This study investigates potential interventions that target the mechanisms of aging, aligning with the goal of understanding and addressing the root causes of aging rather than merely treating age-related symptoms.
Huirui Liu, Liyao Sun, Yu Mi ...
· Aging cell
· Eye Hospital, The First Affiliated Hospital of Harbin Medical University, Harbin, China.
· pubmed
Lens epithelial cell (LEC) senescence is one of the key pathological processes of age-related cataract (ARC) and is associated with oxidative stress, mitochondrial dysfunction, and protein aggregation. This study aimed to elucidate the pathogenesis of LEC senescence in ARC. The p...
Lens epithelial cell (LEC) senescence is one of the key pathological processes of age-related cataract (ARC) and is associated with oxidative stress, mitochondrial dysfunction, and protein aggregation. This study aimed to elucidate the pathogenesis of LEC senescence in ARC. The protein expression level of silencing regulatory protein 1 (SIRT1) and aptamer protein (p66Shc) was quantified. Reactive oxygen species (ROS) and mitochondrial superoxide levels were measured to evaluate cellular oxidative stress. Senescence-associated protein expression (p21 and p53) and SA-β-galactosidase staining were employed to assess the aging status of LEC. Targeted metabolic analysis was conducted to explore energy changes during LEC senescence, and mitochondrial morphology and function were assessed in the cell models. The aging and damage conditions of the lens in ARC rats were evaluated through histological staining, transmission electron microscopy, expression of senescence-related proteins, and oxidative stress markers. We comprehensively investigated the downregulation of SIRT1 expression and the upregulation of p66Shc expression in human cataract samples, UVB-induced rat cataract models, and UVB-treated LEC. SIRT1 could alleviate UVB-induced oxidative stress, as well as mitochondrial dysfunction, inhibiting p66Shc expression in LEC. Nicotinamide mononucleotide (NMN) effectively alleviated the abnormal expression of aging-related proteins and inhibited mitochondrial morphological and functional disorders by activating SIRT1. In conclusion, NMN activated SIRT1, inhibiting mitochondrial dysfunction, oxidative stress, and senescence in LEC, delaying lens opacity. This mechanism could be associated with the onset and progression of ARC, providing a new strategy for its prevention and treatment.
Longevity Relevance Analysis
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SIRT1 activation by NMN inhibits lens epithelial cell senescence and mitochondrial dysfunction, potentially delaying age-related cataract progression. The study addresses the underlying mechanisms of cellular senescence and oxidative stress, which are central to the aging process and age-related diseases.
Sen Duan, Qindong Zhang, Jinqiang Zhu ...
· Mesenchymal Stem Cells
· Department of Orthopedics, The First People's Hospital of Pinghu, Jiaxing, Zhejiang Province, China.
· pubmed
This study delves into the rejuvenating effects of SS-31 on aged human Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs), focusing on its potential to restore their diminished osteogenic differentiation capacity, a critical issue in geriatric medicine and bone tissue engineeri...
This study delves into the rejuvenating effects of SS-31 on aged human Bone Marrow-Derived Mesenchymal Stem Cells (BM-MSCs), focusing on its potential to restore their diminished osteogenic differentiation capacity, a critical issue in geriatric medicine and bone tissue engineering. SS-31 significantly improved mitochondrial function, increasing ATP production by 35% and reducing ROS levels by 40% in aged BM-MSCs. Osteogenic differentiation was enhanced, as evidenced by a 2.8-fold increase in ALP activity and a 3.5-fold increase in Alizarin Red S staining intensity. Additionally, SS-31 reduced NOS2 expression by 50%, highlighting its therapeutic potential in age-related bone loss. SS-31 intervention not only normalizes mitochondrial structure and function, reducing ROS levels and enhancing oxygen consumption rates, but also targets the NOS2 gene, a potential drug target, which upon knockdown, leads to a substantial upregulation of osteogenic markers and an improvement in mitochondrial function. In conclusion, the findings of this study highlight the therapeutic potential of SS-31 in reversing the age-related decline in BM-MSC function by specifically inhibiting NOS2 expression and restoring mitochondrial function. This research provides a scientific basis for the development of new treatments for osteoporosis and other age-related bone diseases, emphasizing the importance of targeting mitochondrial function and cellular senescence in regenerative therapies.
Longevity Relevance Analysis
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SS-31 enhances osteogenic differentiation in aged BM-MSCs by restoring mitochondrial function and inhibiting NOS2 expression. This paper is relevant as it addresses the underlying mechanisms of aging by targeting mitochondrial dysfunction and cellular senescence, which are key factors in age-related decline and diseases.
Tae Jun Lee, Andrea Santeford, Kristen M Pitts ...
· Lysophospholipids
· John F. Hardesty, MD Department of Ophthalmology and Visual Sciences, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
· pubmed
Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothes...
Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothesize that apolipoprotein M (ApoM), a lipocalin that binds sphingosine-1-phosphate (S1P), might restore lipid homeostasis and retinal function in AMD. In support, we find that human patients with AMD demonstrate significantly reduced ApoM compared to controls. In mice with impaired retinal cholesterol efflux, ApoM improves retinal pigment epithelium (RPE) function and lipotoxicity in an S1P- and S1P receptor 3-dependent manner. Ultrastructural evidence of enhanced melanosome-lipid droplet interactions led us to hypothesize and demonstrate that ApoM-S1P signaling drives RPE-specific lysosomal lipid catabolism. RPE-specific knockout of lysosomal acid lipase recapitulates features of AMD. Our study defines a novel role for ApoM/S1P signaling in AMD driven by RPE lipotoxicity, mediated by cell-autonomous lysosomal lipid catabolism.
Longevity Relevance Analysis
(4)
Apolipoprotein M (ApoM) improves retinal pigment epithelium function and reduces lipotoxicity in age-related macular degeneration through sphingosine-1-phosphate signaling. The study addresses a potential mechanism underlying age-related macular degeneration, which is linked to aging processes and lipid metabolism, thus contributing to our understanding of age-related diseases.
Sara Picó, Alba Vílchez-Acosta, João Agostinho de Sousa ...
· Cell reports
· Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
· pubmed
In vivo reprogramming through the forced expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) has demonstrated great potential for reversing age-associated phenotypes. However, continuous in vivo OSKM expression has raised safety concerns due to loss of cell identity, decrease in bod...
In vivo reprogramming through the forced expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) has demonstrated great potential for reversing age-associated phenotypes. However, continuous in vivo OSKM expression has raised safety concerns due to loss of cell identity, decrease in body weight, and premature death. Although cyclic short-term or targeted expression of the reprogramming factors can mitigate some of these detrimental effects, systemic rejuvenation of wild-type mice has remained elusive. To improve the fundamental understanding of in vivo reprogramming, we conduct a comparative analysis of various reprogrammable mouse strains across multiple tissues and organs. In addition, we develop reprogrammable mouse strains by avoiding OSKM expression in specific organs or implementing expression approaches within specific cells, thereby offering safer strategies to induce in vivo reprogramming. We hope that these tools will become valuable resources for future research in this field of research with potential implications to human health.
Longevity Relevance Analysis
(4)
The paper claims to develop safer strategies for in vivo reprogramming to potentially reverse age-associated phenotypes. This research is relevant as it addresses the fundamental mechanisms of aging and seeks to provide innovative approaches to rejuvenation, which could have implications for longevity and age-related health.
Haojie Wang, Joost T van Dongen, Jos Hm Schippers
· Journal of experimental botany
· Department of Molecular Genetics, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, 06466 Seeland, Germany.
· pubmed
Protein homeostasis controlled by the 26S proteasome plays a pivotal role in the adaption of plants to environmental stress, contributing to survival and longevity. During ageing in animals, proteasome activity declines resulting in senescence, however, in plants this is so far l...
Protein homeostasis controlled by the 26S proteasome plays a pivotal role in the adaption of plants to environmental stress, contributing to survival and longevity. During ageing in animals, proteasome activity declines resulting in senescence, however, in plants this is so far largely unexplored. Both in Arabidopsis and barley we found that genes encoding for proteasomal subunits are upregulated at the transcript level during the onset of leaf senescence. In contrast, at the protein level a decrease in proteasomal subunit abundance was observed. Moreover, in Arabidopsis 26S proteasome capacity deteriorates with leaf age, while 20S proteasome activity increases. In contrast, in barley a potential increase in proteasome activity was observed with age. As ribosome-associated RNAs levels of proteasomal subunits increase in Arabidopsis during senescence, it suggests a high-turnover. Furthermore, chemical inhibition of the proteasome results in accelerated leaf senescence in Arabidopsis and barley. In Arabidopsis, 26S proteasome activity could be restored by external cytokinin application, resulting in delayed senescence. Finally, we identified several senescence-associated transcription factors that acts as novel transcriptional regulator of proteasomal genes in Arabidopsis. Taken together, this work provides new insights into the dynamic regulation of proteasome activity which deepens our understanding on leaf senescence in plants.
Longevity Relevance Analysis
(4)
The paper claims that the regulation of 26S proteasome activity and abundance during leaf senescence is crucial for understanding plant longevity. This research is relevant as it explores the mechanisms of protein homeostasis and its role in plant aging, contributing to the broader understanding of longevity in biological systems.
Renard, T., Boseret, M., Aron, S.
· evolutionary biology
· Universite Libre de Bruxelles
· biorxiv
Epigenetic alterations are a hallmark of aging. Age-specific DNA methylation patterns can be used to create "epigenetic clocks", i.e., machine-learning algorithms that use methylation data from multiple genomic sites to predict chronological age (i.e., the number of years or time...
Epigenetic alterations are a hallmark of aging. Age-specific DNA methylation patterns can be used to create "epigenetic clocks", i.e., machine-learning algorithms that use methylation data from multiple genomic sites to predict chronological age (i.e., the number of years or time passed since birth) or biological age (i.e., a functional metric of biological integrity). Epigenetic clocks have been developed for mammals and, to a lesser extent, for birds, fish, amphibians, crustaceans, and insects. At present, all epigenetic clocks utilise C5-methylcytosine (5mC), a prevalent DNA methylation mark in vertebrates. However, in some species, 5mC marks are rare or even undetectable. Here, we describe epigenetic clocks based on N6-methyladenine (6mA), a DNA methylation mark whose role in aging has remained unexplored. Using Oxford Nanopore Technology (ONT) sequencing, we measured genome-wide base-resolution levels of 6mA and 5mC in males of the buff-tailed bumblebee Bombus terrestris (n = 24). We constructed a series of epigenetic clocks using age-specific patterns in 6mA or 5mC. For each clock, predicted epigenetic age and chronological age were highly correlated. Furthermore, we pharmacologically increased individual lifespan with pharmacological agents and showed that, for individuals whose lifespan had been pharmacologically increased, each clock predicted younger epigenetic age than chronological age, indicating that the clocks captured signals of biological aging. Our results demonstrate that 6mA patterns can be used to build epigenetic clocks that accurately predict both chronological and biological age in animals, paving the way toward the use of 6mA as a reliable biomarker of aging.
Longevity Relevance Analysis
(4)
The paper claims that N6-methyladenine (6mA) patterns can be used to construct epigenetic clocks that accurately predict both chronological and biological age in the bumblebee Bombus terrestris. This research is relevant as it explores a novel epigenetic marker for aging, potentially contributing to our understanding of biological aging mechanisms and biomarkers, which are crucial for longevity research.
Cade Ward, Michael M Shahid, Grace Hohman ...
· Advanced biology
· Department of Chemistry, Illinois State University, Normal, IL, 61790, USA.
· pubmed
While aging is a natural biological process, it is associated with a greater risk for multiple diseases, including cancer, neurodegeneration, and cardiovascular disease. Thus, it is important to study the biochemical mechanisms involved in aging to understand how to treat and pre...
While aging is a natural biological process, it is associated with a greater risk for multiple diseases, including cancer, neurodegeneration, and cardiovascular disease. Thus, it is important to study the biochemical mechanisms involved in aging to understand how to treat and prevent these health conditions. The discovery that calorie restriction (CR) promoted longevity in various organisms is a major breakthrough for aging research. Molecular studies of CR have revealed that it mediates its anti-aging effects by activating key signaling pathways, including the AMPK pathway. This pathway is important for regulating various processes, including energy homeostasis, metabolism, and proteostasis. Despite the advantages associated with CR, this practice can have detrimental effects, including decreased liver, body, and muscle mass. Additionally, CR is difficult to track and maintain, limiting its long-term potential. Interestingly, direct activation of the AMPK pathway offers a potential approach to increase longevity and quality of life without dietary restrictions. Remarkably, a recent discovery revealed that lithocholic acid (LCA), a metabolite from bile acid, could directly activate the AMPK pathway. Activation of the AMPK pathway by LCA leads to the beneficial effects of CR without the negative effects. These recent findings point to the possibility that supplementation of specific doses of LCA could offer a novel approach to induce anti-aging pathways that lead to increased longevity and improved quality of life.
Longevity Relevance Analysis
(4)
Lithocholic acid can activate the AMPK pathway to induce anti-aging effects similar to calorie restriction without its negative consequences. The paper addresses mechanisms of aging and proposes a potential intervention that targets the root causes of aging rather than merely addressing age-related diseases.
Qiao Li, Zonghao Qian, Yuzhen Huang ...
· Cellular Senescence
· Experimental Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China.
· pubmed
Cardiovascular disease (CVD) is a major cause of mortality, especially in the aging population. Aging is one of the main risk factors contributing to CVD, leading to early mortality and a decline in the quality of life. Vascular aging is closely linked with atherosclerosis, diabe...
Cardiovascular disease (CVD) is a major cause of mortality, especially in the aging population. Aging is one of the main risk factors contributing to CVD, leading to early mortality and a decline in the quality of life. Vascular aging is closely linked with atherosclerosis, diabetes, hypertension, stroke, heart failure, and peripheral arterial diseases. Elucidating the cellular and molecular mechanisms underlying vascular aging help to develop therapeutic strategies that can address age-related vascular diseases and decrease the rate of morbidity and mortality among the older population. Endothelial cells located on the interior layer of blood vessels. Intima layers of vascular vessels are damaged and remodeled during vascular aging. The dysfunction of smooth muscle cells and endothelial cells plays key roles in vascular aging. Common pathological changes during vascular aging include arterial stiffness, calcification, and atherosclerosis. Endothelial cell senescence is driven by complex underlying mechanisms. The complex regulation of aging and antiaging network in endothelial cells involve several factors, such as Klotho protein, nitric oxide, fibroblast growth factor 21 (FGF21), and SIRT family members.
Longevity Relevance Analysis
(4)
The paper explores the mechanisms of endothelial senescence and vascular aging, which are critical factors in age-related diseases. Understanding these mechanisms can contribute to developing therapeutic strategies aimed at addressing the root causes of vascular aging and improving longevity.
Xiaoyue Mei, Hannaneh Kabir, Michael J Conboy ...
· GeroScience
· Department of Bioengineering and QB3 Institute, UC Berkeley, Berkeley, CA, 94720, USA.
· pubmed
Biological aging is a complex non-linear process, with markedly distinct starting and end points, yet the biomarkers of its progression remain elusive. A key assumption of most machine learning (ML) approaches for age clocks is that predictive biomedical features can be identifie...
Biological aging is a complex non-linear process, with markedly distinct starting and end points, yet the biomarkers of its progression remain elusive. A key assumption of most machine learning (ML) approaches for age clocks is that predictive biomedical features can be identified via mathematical transformations of data to favor a linear transition from start to end, even if they erase any natural biological pattern. It is given that expected correlations, e.g., time lived (age) and time left to live (mortality), would persist in such mathematically optimized models, biologically meaningful or not. Here, we further clarify the workings of the clocks, explain the trade-off between mathematical optimization and biological interpretability, and discuss a hallmark of aging, inflammaging, that age clocks struggle to detect. We expand on the negative consequences of incoherence in linear models where some DNA methylation (DNAm) features increase with aging and disease, while others correspondingly decrease, yet positive weights are assigned to both. We quantify the misalignment between major DNAm clocks and actual changes in DNAm, providing an interactive visualization of these errors for each model. We demonstrate that major conventional age clocks are both incoherent and skewed toward leukocyte fractions and that rectifying incoherence makes the model balanced and not skewed toward neutrophils and better detects inflammaging. We briefly outline non-linear ML age clocks and the advantages of identifying a natural trajectory of aging directly from the primary data.
Longevity Relevance Analysis
(4)
The paper claims that conventional age clocks are incoherent and skewed, and that rectifying these issues can improve the detection of biological aging markers. This research addresses the fundamental mechanisms of biological aging and seeks to improve the accuracy of age prediction models, which is crucial for understanding and potentially intervening in the aging process.
Seungmee Park, Yishi Jin, Andrew D Chisholm
· Genetics
· Department of Neurobiology, School of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA.
· pubmed
Neurons maintain their morphology over prolonged periods of adult life with limited regenerative capacity. Among the various factors that shape neuronal morphology, lipids function as membrane components, signaling molecules, and regulators of synaptic plasticity. Here, we tested...
Neurons maintain their morphology over prolonged periods of adult life with limited regenerative capacity. Among the various factors that shape neuronal morphology, lipids function as membrane components, signaling molecules, and regulators of synaptic plasticity. Here, we tested genes involved in phospholipid biosynthesis and identified their roles in axon regrowth and maintenance. CEPT-2 and EPT-1 are enzymes catalyzing the final steps in the de novo phospholipid synthesis (Kennedy) pathway. Loss of function mutants of cept-2 or ept-1 show reduced axon regrowth and failure to maintain axon morphology. We demonstrate that CEPT-2 is required cell-autonomously to prevent age-related axonal morphology defects. We further investigated genetic interactions of cept-2 or ept-1 with dip-2, a conserved regulator of lipid metabolism that affects axon morphology maintenance and regrowth after injury. Loss of function in dip-2 led to suppression of axon regrowth defects observed in either cept-2 or ept-2 mutants, suggesting that DIP-2 acts to counterbalance phospholipid synthesis. Our findings reveal the genetic regulation of lipid metabolism as critical for axon maintenance following injury and during aging.
Longevity Relevance Analysis
(4)
The paper claims that genetic regulation of lipid metabolism is critical for axon maintenance following injury and during aging. This research addresses mechanisms underlying neuronal integrity and regeneration, which are essential for understanding and potentially mitigating age-related decline in neuronal function.
Michela Libergoli, Albert E Almada
· Rejuvenation research
· Department of Orthopaedic Surgery, Keck School of Medicine, University of Southern California (USC), Los Angeles, California, USA.
· pubmed
Aging is an unavoidable process associated with a progressive decline of muscle mass, strength, and regenerative ability. Satellite cells are a muscle stem cell (MuSC) population that plays a key role in mammalian muscle regeneration, by awakening from quiescence and then migrati...
Aging is an unavoidable process associated with a progressive decline of muscle mass, strength, and regenerative ability. Satellite cells are a muscle stem cell (MuSC) population that plays a key role in mammalian muscle regeneration, by awakening from quiescence and then migrating to sites of damage, expanding in number to generate progenitor cells, and then either differentiating to rebuild the muscle tissue or self-renewing to repopulate the stem cell pool. Emerging evidence suggests that the aging process impairs the activation potential and the regenerative capacity of MuSCs. This review explores some of the recent discoveries of how mis-regulation of intrinsic and extrinsic mechanisms drive the decline of MuSC function in aging muscles, and we discuss new strategies to rejuvenate aged MuSC function for regenerative medicine. Understanding these processes will speed up the development of novel therapeutics for counteracting muscle loss and improve muscle healing in the elderly.
Longevity Relevance Analysis
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The paper discusses the mechanisms driving the decline of muscle stem cell function in aging and explores strategies for rejuvenation. This research is relevant as it addresses the underlying biological processes of aging and seeks to develop therapeutic approaches to counteract age-related muscle degeneration.
Guan Wang, Anying Song, Qiong A Wang
· Nature reviews. Endocrinology
· Department of Molecular & Cellular Endocrinology, Arthur Riggs Diabetes and Metabolism Research Institute, City of Hope Medical Center, Duarte, CA, USA.
· pubmed
Adipose tissue, a pivotal player in whole-body energy homeostasis and insulin sensitivity, undergoes considerable remodelling throughout the ageing process, a facet that has garnered little attention until the past decade. This Review comprehensively summarizes the dynamic metabo...
Adipose tissue, a pivotal player in whole-body energy homeostasis and insulin sensitivity, undergoes considerable remodelling throughout the ageing process, a facet that has garnered little attention until the past decade. This Review comprehensively summarizes the dynamic metabolic, cellular and functional changes that occur in white and thermogenic adipose tissue during distinct ageing stages, across different adipose tissue depots. We emphasize the influence of ageing on different cell types within adipose tissue, including adipocytes, adipocyte progenitors, immune cells and senescent cells, and their collective effect on adipose tissue function and systemic metabolism. We also decipher the correlation between adipose tissue ageing and prevalent age-related conditions such as metabolic dysfunction-associated fatty liver disease and cardiovascular diseases. Finally, the Review delves into the potential of current anti-ageing interventions to beneficially affect adipose tissue, encompassing caloric restriction, metformin, glucagon-like peptide 1 receptor agonists and senolytics. The discussion extends to the exploration of whether targeting adipose tissue through such interventions could emerge as a prominent therapeutic strategy for mitigating age-related diseases and enhancing the healthspan and lifespan of the ageing population.
Longevity Relevance Analysis
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The paper discusses the implications of adipose tissue ageing on metabolic health and potential interventions to improve healthspan and lifespan. This research is relevant as it addresses the underlying mechanisms of ageing and explores therapeutic strategies that could mitigate age-related diseases.
The increasing global population aging has made the prevention and control of aging-related diseases a major public health challenge in the twenty-first century. Nicotinamide mononucleotide (NMN), as a precursor of nicotinamide adenine dinucleotide (NAD
The increasing global population aging has made the prevention and control of aging-related diseases a major public health challenge in the twenty-first century. Nicotinamide mononucleotide (NMN), as a precursor of nicotinamide adenine dinucleotide (NAD
Longevity Relevance Analysis
(4)
The paper discusses the biological properties and anti-aging mechanisms of nicotinamide mononucleotide (NMN) as a potential intervention in aging. NMN is directly linked to NAD+ metabolism, which is crucial for cellular health and longevity, addressing the root causes of aging.
Sakshi Chaudhary, Mani Raj Chaudhary, Manoj Kumar Jena ...
· Biogerontology
· Department of Biochemistry, School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, Punjab, 144411, India.
· pubmed
Geroprotectors, a class of compounds that ameliorate molecular, cellular, or physiological aging-related alterations, have garnered significant attention in the quest to promote healthy aging and extend the human health span. Among these, Calorie Restriction Mimetics (CRMs) have ...
Geroprotectors, a class of compounds that ameliorate molecular, cellular, or physiological aging-related alterations, have garnered significant attention in the quest to promote healthy aging and extend the human health span. Among these, Calorie Restriction Mimetics (CRMs) have emerged as promising candidates due to their potential to mimic the benefits of calorie restriction, a dietary approach involving reduced calorie intake without malnutrition. Prospective CRMs may include biguanides (metformin and aminoguanidine), which exert effects on the insulin signaling pathway; rapamycin, which interacts with mTOR signaling pathways; and stilbenes (resveratrol), which influences stress signaling pathways and promotes the activation of AMPK, impacting mitochondrial metabolism in addition to the activity of FOXO and sirtuin. Other compounds, such as glycolytic inhibitors, carbohydrate and lipid absorption blockers, polyamines, and polyphenols, which collectively modulate pathways regulating the effects of free radicals, are also under consideration. To propose prospective geroprotective strategies, this article focuses on analyzing the functions of potential CRMs and their mechanisms demonstrating health benefits, the same as that of CR (Calorie Restriction), but without undesirable side effects.
Longevity Relevance Analysis
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The paper discusses the potential of Calorie Restriction Mimetics (CRMs) to mimic the health benefits of calorie restriction in promoting healthy aging. This research is relevant as it addresses mechanisms that could mitigate aging-related alterations and promote longevity.
Indi P Joore, Sawsan Shehata, Irena Muffels ...
· DNA, Mitochondrial
· Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
· pubmed
Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with...
Mutations in the mitochondrial genome can cause maternally inherited diseases, cancer, and aging-related conditions. Recent technological progress now enables the creation and correction of mutations in the mitochondrial genome, but it remains relatively unknown how patients with primary mitochondrial disease can benefit from this technology. Here, we demonstrate the potential of the double-stranded DNA deaminase toxin A-derived cytosine base editor (DdCBE) to develop disease models and therapeutic strategies for mitochondrial disease in primary human cells. Introduction of the m.15150G > A mutation in liver organoids resulted in organoid lines with varying degrees of heteroplasmy and correspondingly reduced ATP production, providing a unique model to study functional consequences of different levels of heteroplasmy of this mutation. Correction of the m.4291T > C mutation in patient-derived fibroblasts restored mitochondrial membrane potential. DdCBE generated sustainable edits with high specificity and product purity. To prepare for clinical application, we found that mRNA-mediated mitochondrial base editing resulted in increased efficiency and cellular viability compared to DNA-mediated editing. Moreover, we showed efficient delivery of the mRNA mitochondrial base editors using lipid nanoparticles, which is currently the most advanced non-viral in vivo delivery system for gene products. Our study thus demonstrates the potential of mitochondrial base editing to not only generate unique in vitro models to study these diseases, but also to functionally correct mitochondrial mutations in patient-derived cells for future therapeutic purposes.
Longevity Relevance Analysis
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The paper demonstrates the potential of mitochondrial base editing to correct pathogenic mutations in patient-derived cells. This research is relevant as it addresses the root causes of mitochondrial diseases, which are linked to aging and age-related conditions, potentially offering therapeutic strategies that could impact longevity.
Rui Zhao, Taili Zhao, Tingting Shi ...
· Biogerontology
· School of Bioengineering, Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, China.
· pubmed
Jingfang Granule (JFG), a traditional Chinese medicine preparation, is widely used in clinical practice. It has been shown to extend both lifespan and healthspan in the Caenorhabditis elegans model. However, the molecular mechanisms of its main constituents and their targets rema...
Jingfang Granule (JFG), a traditional Chinese medicine preparation, is widely used in clinical practice. It has been shown to extend both lifespan and healthspan in the Caenorhabditis elegans model. However, the molecular mechanisms of its main constituents and their targets remain unclear. In this study, through network pharmacology, molecular docking, and experiments on C. elegans including lifespan assays and stress resistance assays, the bioactive compounds of JFG and their targets were screened. Network analysis identified a total of 187 candidate components and 150 drug-disease related targets, among which TP53, STAT3, IL6, TNF, AKT1, ESR1, CCND1, BCL2, MAPK1, and MAPK3 were the core nodes. Gene Ontology (GO) enrichment analysis revealed that these targets were mainly involved in aging-related and anti-apoptotic processes. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis suggested that the AGE-RAGE signaling pathway, which is crucial in diabetic complications, might be involved. Experiments on Caenorhabditis elegans further confirmed that neohesperidin, kaempferol, and stigmasterol in Jingfang Granule exhibited good anti-aging effects and stress resistance. They could extend the lifespan of Caenorhabditis elegans by activating the target genes of the transcription factors DAF-16, HSF-1, and SKN-1. By combining the strategies of network pharmacology and molecular biology, this study elucidated the anti-aging mechanisms of the Jingfang Granule formula and its bioactive compounds. Therefore, the Jingfang Granule formula and its bioactive compounds hold potential for lifespan extension, healthspan improvement, and enhanced stress resistance.
Longevity Relevance Analysis
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The study identifies bioactive compounds in Jingfang Granules that can extend lifespan and improve stress resistance in C. elegans. The research is relevant as it explores potential mechanisms for lifespan extension and healthspan improvement, addressing the root causes of aging.
Alyssa C Rodriguez, Emiko A Kramár, Agatha S Augustynski ...
· The Journal of neuroscience : the official journal of the Society for Neuroscience
· Department of Neurobiology and Behavior, University of California, Irvine; Irvine, California; 92697, USA.
· pubmed
Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical for its deacetylase activity in transcription...
Long-term memory formation is negatively regulated by histone deacetylase 3 (HDAC3), a transcriptional repressor. Emerging evidence suggests that post-translational phosphorylation of HDAC3 at its serine 424 (S424) residue is critical for its deacetylase activity in transcription. However, it remains unknown if HDAC3 S424 phosphorylation regulates the ability of HDAC3 to modulate long-term memory formation. To examine the functionality of S424, we expressed an HDAC3-S424D phospho-mimic mutant (constitutively active form) or an HDAC3-S424A phospho-null mutant (deacetylase dead form) in the dorsal hippocampus of mice. We assessed the functional consequence of these mutants on long-term memory (LTM) formation and long-term potentiation (LTP) in young adult male mice. We also assessed whether the HDAC3-S424A mutant could ameliorate age-related deficits in LTM and LTP in aging male and female mice. Results demonstrate that young adult male mice expressing the HDAC3-S424D phospho-mimic mutant in dorsal hippocampus exhibit significantly impaired LTM and LTP. In contrast, the HDAC3-S424A phospho-null mutant expressed in the hippocampus of young adult male mice enabled the transformation of subthreshold learning into robust LTM and enhanced LTP. Similarly, expression of the HDAC3-S424A mutant enabled LTM formation and enhanced LTP in aging male and aging female mice. Overall, these findings demonstrate that HDAC3 S424 is a pivotal residue that has the ability to bidirectionally regulate synaptic plasticity and LTM formation in the adult and aging brain.
Longevity Relevance Analysis
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The paper claims that HDAC3 S424 phosphorylation regulates long-term memory formation and synaptic plasticity in both young and aging mice. This research is relevant as it explores mechanisms that could potentially influence cognitive decline associated with aging, addressing a fundamental aspect of age-related cognitive impairment.
Smith, S. A., Pease, J. B., Carruthers, T. ...
· evolutionary biology
· Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI 48109, USA
· biorxiv
Many long-lived plant species exhibit notable patterns in phylogenies, such as short molecular branch lengths and high gene-tree conflict. However, it is not clear what biological properties of long-lived plant species or concomitant processes acting within these lineages generat...
Many long-lived plant species exhibit notable patterns in phylogenies, such as short molecular branch lengths and high gene-tree conflict. However, it is not clear what biological properties of long-lived plant species or concomitant processes acting within these lineages generate these patterns. To explore this mystery, we implemented an agent-based model and conducted simulations to investigate how longevity affects molecular evolution and population dynamics. Through these simulations, we demonstrated that the patterns exhibited in empirical datasets for long-lived species can be explained by their lifespan and overlapping generations. We also show that somatic mutations can exacerbate these patterns, although evidence for substantive rates in empirical systems high enough to impact phylogenetic patterns is scarce. We discuss several empirical datasets containing life history shifts that exhibit diverse phylogenomic patterns. The variation produced through different parameterizations of our simulations reflects the diversity of patterns found in empirical datasets. Our results have broad implications for phylogenomic patterns and population genetics in general, as well as for specifically explaining patterns of evolution in long-lived lineages.
Longevity Relevance Analysis
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The paper claims that longevity in plants affects molecular evolution and population dynamics, explaining observed phylogenomic patterns. The research explores biological properties of long-lived species, contributing to understanding the mechanisms of longevity, which is relevant to the broader field of aging research.
Metformin is a widely used antidiabetic agent for obesity-related type 2 diabetes mellitus, providing significant health benefits such as reduced blood glucose levels and body weight. Emerging evidence suggests that metformin may play a beneficial role in delaying aging. However,...
Metformin is a widely used antidiabetic agent for obesity-related type 2 diabetes mellitus, providing significant health benefits such as reduced blood glucose levels and body weight. Emerging evidence suggests that metformin may play a beneficial role in delaying aging. However, the causal relationship between metformin use and frailty index (FI) remains uncertain and warrants further investigation. This study aimed to explore the genetically predicted causal relationship between metformin targets and FI.
Longevity Relevance Analysis
(4)
The paper claims that metformin use is causally linked to a reduced frailty index. This research is relevant as it explores a potential intervention that may address underlying mechanisms of aging and frailty, contributing to the understanding of longevity.
Joost Verduijn, Kelly Coutant, Mitchell E Fane ...
· Cell death and differentiation
· Cancer Signaling and Microenvironment Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
· pubmed
Along with organismal aging, multiple compartments of the immune system undergo a progressive functional degeneration that may contribute to - or at least allow for - disease, a scenario that is commonly known as "immunosenescence". While not all immune cell populations suffer fr...
Along with organismal aging, multiple compartments of the immune system undergo a progressive functional degeneration that may contribute to - or at least allow for - disease, a scenario that is commonly known as "immunosenescence". While not all immune cell populations suffer from organismal aging through similar mechanisms, immunosenescence appears to involve numerical alterations in specific immune cell types that - at least in some settings - result from the unscheduled activation of regulated cell death (RCD), often along with unbalanced hematopoietic output downstream of thymic involution and bone marrow defects. Here, we critically discuss core RCD mechanisms including apoptosis, necroptosis, ferroptosis, pyroptosis and NETosis as key regulators of global immune homeostasis in the context of immunosenescence.
Longevity Relevance Analysis
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The paper discusses the role of regulated cell death mechanisms in the context of immunosenescence and their impact on immune system degeneration with aging. This research is relevant as it addresses underlying mechanisms of aging that contribute to immune dysfunction, which is a critical aspect of longevity and age-related diseases.
Aubrey Converse, Madeline J Perry, Shweta S Dipali ...
· PLoS biology
· Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
· pubmed
The ovary is one of the first organs to exhibit signs of aging, characterized by reduced tissue function, chronic inflammation, and fibrosis. Multinucleated giant cells (MNGCs), formed by macrophage fusion, typically occur in chronic immune pathologies, including infectious and n...
The ovary is one of the first organs to exhibit signs of aging, characterized by reduced tissue function, chronic inflammation, and fibrosis. Multinucleated giant cells (MNGCs), formed by macrophage fusion, typically occur in chronic immune pathologies, including infectious and non-infectious granulomas and the foreign body response, but are also observed in the aging ovary. The function and consequence of ovarian MNGCs remain unknown as their biological activity is highly context-dependent, and their large size has limited their isolation and analysis through technologies such as single-cell RNA sequencing. In this study, we define ovarian MNGCs through a deep analysis of their presence across age and species using advanced imaging technologies as well as their unique transcriptome using laser capture microdissection. MNGCs form complex interconnected networks that increase with age in both mouse and nonhuman primate ovaries. MNGCs are characterized by high Gpnmb expression, a putative marker of ovarian and non-ovarian MNGCs. Pathway analysis highlighted functions in apoptotic cell clearance, lipid metabolism, proteolysis, immune processes, and increased oxidative phosphorylation and antioxidant activity. Thus, MNGCs have signatures related to degradative processes, immune function, and high metabolic activity. These processes were enriched in MNGCs compared to primary ovarian macrophages, suggesting discrete functionality. MNGCs express CD4 and colocalize with T-cells, which were enriched in regions of MNGCs, indicative of a close interaction between these immune cell types. These findings implicate MNGCs in modulation of the ovarian immune landscape during aging given their high penetrance and unique molecular signature that supports degradative and immune functions.
Longevity Relevance Analysis
(4)
The paper claims that multinucleated giant cells (MNGCs) in the aging ovary have unique immune and degradation-associated molecular signatures that may influence ovarian function and aging. This research is relevant as it explores the biological mechanisms underlying ovarian aging, potentially addressing root causes of age-related decline in reproductive function.
Irish, S. D., Kimberley, A., Immler, S. ...
· evolutionary biology
· University of East Anglia
· biorxiv
Dietary restriction (DR) extends lifespan in animals and plants, but its evolutionary causes are elusive. Adaptive hypotheses posit that DR extends lifespan because organisms reallocate resources from reproduction to survival (\"disposable soma\") or recycle cellular waste to max...
Dietary restriction (DR) extends lifespan in animals and plants, but its evolutionary causes are elusive. Adaptive hypotheses posit that DR extends lifespan because organisms reallocate resources from reproduction to survival (\"disposable soma\") or recycle cellular waste to maximize either their immediate reproduction (\"nutrient recycling\") or survival (\"clean cupboards\"). We developed an experimental paradigm that tricks Caenorhabditis elegans nematodes into increasing their reproductive effort under DR via food odour, thus allowing us to test these hypotheses. We found that experimentally increased reproduction under DR does not affect immediate or long-term survival benefits compared to DR animals that did not reproduce, thus refuting all three adaptive hypotheses. Our data suggest that a large part of suppressed fertility under DR is a result of organisms refraining from producing offspring in a poor environment. We developed a model based on Hamiltonian forces of selection to show that lifespan extension under DR evolves because DR suppresses fertility, directly increasing selection against mortality in DR environment. Our analytical approach suggests that DR-driven lifespan extension can evolve under a broader range of conditions not previously anticipated, such as a relaxed need for physiological or genetic trade-offs. Instead, we show how reduced survival on plentiful food can evolve via mutation accumulation.
Longevity Relevance Analysis
(4)
The paper claims that lifespan extension under dietary restriction evolves due to suppressed fertility rather than resource reallocation. This research is relevant as it explores the evolutionary mechanisms behind lifespan extension, contributing to our understanding of aging and longevity.
Chenji Li, Sadegh Dabiri, Arezoo M Ardekani
· Fluids and barriers of the CNS
· School of Mechanical Engineering, Purdue University, West Lafayette, IN, 47906, USA.
· pubmed
The glymphatic theory suggests a convective transport mechanism through brain tissue, which has significant implications for both brain waste clearance and drug delivery. However, the existence and driving mechanisms of directional convection from periarterial to perivenous space...
The glymphatic theory suggests a convective transport mechanism through brain tissue, which has significant implications for both brain waste clearance and drug delivery. However, the existence and driving mechanisms of directional convection from periarterial to perivenous spaces remain debated. Additionally, the role of brain tissue stiffness in parenchymal transport remains unclear, as experiments have reported varying trends in stiffness changes in cases of aging and neurodegenerative diseases. Previous mechanistic models often simplify or neglect perivenous spaces and venous deformation, raising questions about whether arterial vasomotion alone can effectively drive artery-to-vein transport. In this study, we propose a multiphysics model that incorporates the poroelastic nature of brain tissue, capturing the dynamic interactions between periarterial and perivenous spaces. Our results demonstrate that net glymphatic flow sweeps from periarterial space across parenchyma and is modulated by the periarterial-perivenous interactions, leading to higher pressure in periarterial space that drives unidirectional bulk transport from periarterial space to perivenous space. We also show that brain tissue stiffness presents a non-monotonic effect on both the glymphatic transport and its efficiency, with their respective peaks occurring at different stiffness values. Notably, the glymphatic convection rate peaks at physiologically relevant levels of brain stiffness. Furthermore, phase-delayed venous vasomotion is found to enhance glymphatic flow. These findings highlight the critical role of perivascular interactions and provide a framework for exploring brain fluid dynamics and potential therapeutic strategies for neurodegenerative diseases.
Longevity Relevance Analysis
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The study claims that perivascular interactions and brain tissue stiffness modulate glymphatic transport efficiency. The research is relevant as it explores mechanisms that could influence brain health and potentially address underlying processes associated with neurodegenerative diseases, which are significant concerns in the context of aging.
Yu Liu, Meiling Ge, Xina Xiao ...
· Nature aging
· National Clinical Research Center for Geriatrics and Department of Laboratory Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
· pubmed
Age-related changes in circulating metabolites influence systemic physiology and may contribute to diseases such as sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. In this study, we performed comprehe...
Age-related changes in circulating metabolites influence systemic physiology and may contribute to diseases such as sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. In this study, we performed comprehensive plasma metabolomic and lipidomic analyses across two cohorts comprising 1,013 individuals, uncovering the metabolic characteristics of sarcopenia, including a notable decline in plasma sarcosine levels in both aging patients and those with sarcopenia. Functional studies in mice showed that sarcosine helps maintain muscle mass homeostasis during aging, promotes adipose thermogenesis and enhances muscle regeneration. We demonstrate here that sarcosine activated the GCN2 signaling pathway to enhance anti-inflammatory macrophage polarization, promoting adipose thermogenesis and muscle regeneration. These effects may increase energy expenditure and restore metabolic balance to reduce chronic inflammation and improve insulin sensitivity, which are crucial for managing sarcopenia. This study underscores the potential of sarcosine supplementation as an adjunctive strategy via macrophage modulation for preventing sarcopenia in older adults.
Longevity Relevance Analysis
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Sarcosine supplementation may enhance muscle regeneration and adipose thermogenesis by activating anti-inflammatory macrophages. The study addresses metabolic dysregulation in sarcopenia, which is a significant age-related condition, and explores a potential intervention that could mitigate its effects, thus contributing to longevity research.
Gabriel Meca-Laguna, Michael Qiu, Yafei Hou ...
· Aging cell
· Lifespan Research Institute, Mountain View, California, USA.
· pubmed
The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet...
The accumulation of senescent cells (SEN) with aging produces a chronic inflammatory state that accelerates age-related diseases. Eliminating SEN has been shown to delay, prevent, and in some cases reverse aging in animal disease models and extend lifespan. There is thus an unmet clinical need to identify and target SEN while sparing healthy cells. Here, we show that Lysosomal-Associated Membrane Protein 1 (LAMP1) is a membrane-specific biomarker of cellular senescence. We have validated selective LAMP1 upregulation in SEN in human and mouse cells. Lamp1
Longevity Relevance Analysis
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LAMP1 is identified as a membrane-specific biomarker of cellular senescence. This research addresses the root cause of aging by focusing on the identification and potential targeting of senescent cells, which is crucial for developing therapies aimed at extending healthspan and lifespan.
Jones, S. W., Shigdar, S., Tollitt, B. R. ...
· bioengineering
· University of Liverpool
· biorxiv
Microgravity provides a unique model for understanding accelerated skeletal muscle loss, and potentially a model of muscle ageing, offering insights into the molecular mechanisms underlying reductions in muscle mass and function. During spaceflight, astronauts experience pronounc...
Microgravity provides a unique model for understanding accelerated skeletal muscle loss, and potentially a model of muscle ageing, offering insights into the molecular mechanisms underlying reductions in muscle mass and function. During spaceflight, astronauts experience pronounced skeletal muscle atrophy. These effects appear similar to age-related muscle decline on Earth but on a significantly shorter timescale. Despite the incorporation of daily aerobic and resistance exercise on the International Space Station (ISS), countermeasures remain suboptimal, reflecting analogous challenges in exercise efficacy observed in ageing populations. The MicroAge Mission aimed to exploit microgravity conditions aboard the ISS to determine whether the molecular mechanisms underpinning reduced adaptive responses to contractile activity during ageing are analogous to those induced by spaceflight. The mission also explored proof-of-concept genetic interventions, including overexpression of Heat Shock Protein 10 (HSP10), a mitochondrial chaperone, to mitigate muscle atrophy and functional loss. To conduct these investigations, a tissue-engineering approach was employed to fabricate human skeletal muscle constructs, which were secured to custom-designed, 3D-printed scaffolds. The scaffolds featured integrated microfluidic channels designed to interface with the fluid handling system within the flight hardware. The hardware, developed by Kayser Space Ltd, was specifically designed to interface with the European Space Agency (ESA) Kubik incubator located within the Columbus module of the ISS. This research addresses critical methodological constraints in low Earth orbit (LEO) experimentation, providing a detailed account of pre-flight protocol development, muscle construct biofabrication techniques, and operational considerations. The findings establish a translational framework for future investigations into musculoskeletal degeneration, with implications for therapeutic strategies targeting both terrestrial ageing and astronaut musculoskeletal health.
Longevity Relevance Analysis
(4)
The paper claims that microgravity-induced muscle atrophy shares molecular mechanisms with age-related muscle decline, and explores genetic interventions to mitigate this atrophy. This research is relevant as it addresses the underlying mechanisms of muscle degeneration associated with aging, potentially leading to therapeutic strategies for both aging populations and astronauts.
Basma Abdelkader, Xiang Qun Shi, Wen Bo Sam Zhou ...
· Pain
· The Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC, Canada.
· pubmed
As individuals age, they often experience persistent, unresolved pain, impacting their quality of life. Aging as a process is accompanied by "inflammaging," a state of chronic, low-grade systemic inflammation contributing to various diseases. Understanding the functional link bet...
As individuals age, they often experience persistent, unresolved pain, impacting their quality of life. Aging as a process is accompanied by "inflammaging," a state of chronic, low-grade systemic inflammation contributing to various diseases. Understanding the functional link between inflammaging and age-related development of pain is crucial for identifying novel therapeutic targets. We hypothesized that the circulatory milieu plays a role in regulating pain and that inflammaging contributes to changes in pain behavior with age. To test these hypotheses, we monitored nociception and postsurgical pain in male and female mice aged 3 and 24 months and analyzed their serum proteome, including cytokine/chemokine profiles. Our results demonstrated that compared with young mice, aging mice were hyposensitive to mechanical stimulation, yet their pain response to incision was aggravated and prolonged. Serum proteomic analysis revealed sex-specific inflammaging patterns. To explore the link between inflammaging and age-related alteration in pain behavior, we applied a rejuvenation strategy by transferring serum from 3-month-old mice to 19- to 21-month-old mice. Young serum normalized mechanical sensitivity in aged mice, alleviated postsurgical mechanical pain, and promoted recovery. Alongside the improvements in pain behavior phenotype, young serum recalibrated the aging serum profile. It reduced age-associated increases of cytokine/chemokine levels in male mice and rescued age-related, female-selective downregulation of inflammatory pathways such as liver X receptor/retinoid X receptor activation, D24-dehydrocholesterol reductase, and complement signaling. Our findings suggest that the circulatory environment, notably inflammaging, plays a significant role in altered pain behavior of aging mice. The sex-specific signature of age-dependent systemic inflammation highlights the importance of investigating inflammaging through the lens of sexual dimorphism.
Longevity Relevance Analysis
(4)
The paper claims that rejuvenation through serum transfer can alleviate prolonged postsurgical pain in aging mice by mitigating the effects of inflammaging. This research addresses the underlying mechanisms of aging-related pain and inflammation, contributing to the understanding of potential therapeutic targets for age-related conditions.
Parast, S., Wang, S., Iwanaszko, M. ...
· molecular biology
· Simpson Querrey Institute for Epigenetics, Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine; Chicago, IL 6
· biorxiv
Transcription elongation factors control post-initiation steps of gene expression by RNA polymerase II (RNAPII). We have established distinct mechanistic roles for the essential elongation factors PAF1, NELF, SPT5, SPT6, and the Super Elongaiton Complex (SEC) via acute depletion ...
Transcription elongation factors control post-initiation steps of gene expression by RNA polymerase II (RNAPII). We have established distinct mechanistic roles for the essential elongation factors PAF1, NELF, SPT5, SPT6, and the Super Elongaiton Complex (SEC) via acute depletion of each individually in auxin-inducible degron lines. Here, we leverage these degron lines to explore the regulatory intersection oftranscription elongation control and pre-mRNA processing. Integrating long- and short-read RNA-seq data to quantify transcript isoform usage at single-molecule resolution, we identify elongation factor-specific RNA processing regulons including a cellular senescence-enriched regulon shared by NELF and SPT6. We then show that long-term depletion of NELF or SPT6 results in reversible growth arrest following early upregulation of a small group of genes, which include the senescence-associated genes CDKN1A (p21) and CCN2. We perform genetic suppressor screens that implicate the elongation factor Elongin A (ELOA) in NELF or SPT6 depletion-induced growth arrest. ELOA loss suppresses NELF depletion-induced pre-mRNA processing defects and the 3-prime extension of RNAPII occupancy past transcription end sites (TES) at genes induced by NELF depletion. ELOA also occupies TES-proximal regions under normal conditions, and acute ELOA depletion results in a loss of RNAPII processivity at the 3-prime end of genes, opposing the effects of NELF or SPT6 depletion. Finally, we demonstrate that genetic loss of ELOA confers a growth advantage to aging human primary dermal fibroblasts. These findings establish the existence of novel ELOA-dependent mechanisms regulating transcription maturation, and links these mechanisms to the complex phenomena of cellular senescence and aging.
Longevity Relevance Analysis
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The paper claims that the elongation factor ELOA regulates transcription maturation and is linked to cellular senescence and aging. This research is relevant as it explores mechanisms that could contribute to understanding the root causes of aging and cellular senescence, potentially offering insights into lifespan extension.
Zhu, K., Cheng, G., Ren, Y. ...
· cell biology
· Tohoku University
· biorxiv
Aneuploid cells are known to increase with age. Previously, we demonstrated that aneuploid cells increase in fibroblasts from aged mice due to chromosomal instability (CIN), which is caused by oxidative stress. It is unclear whether this phenomenon also occurs in human cells, whi...
Aneuploid cells are known to increase with age. Previously, we demonstrated that aneuploid cells increase in fibroblasts from aged mice due to chromosomal instability (CIN), which is caused by oxidative stress. It is unclear whether this phenomenon also occurs in human cells, which are more resistant to oxidative stress than mouse cells. Here, we found that fibroblasts from aged individuals exhibited an increase in aneuploid cells. The frequency of chromosome missegregation and micronuclei increased in these cells, indicating CIN. A DNA fiber assay revealed the presence of replication stress, accompanied by an increase in 53BP1 nuclear bodies and ultrafine bridges. Increased levels of reactive oxygen species derived from mitochondria, along with reduced mitochondrial membrane potential, imply that these cells experienced oxidative stress due to mitochondrial functional decline. Antioxidant treatment reduced the frequency of chromosome missegregation and micronuclei, suggesting that oxidative stress causes CIN. Oxidative stress also causes replication stress, which precedes CIN. Spindle microtubules were stabilized in fibroblasts from aged individuals, which was alleviated by antioxidant treatment. Taken together, these findings suggest that aging-related CIN in human fibroblasts is caused by oxidative stress associated with mitochondrial dysfunction, which induces replication stress that in turn causes CIN through microtubule stabilization. Although human fibroblasts are more resistant to the ambient oxygen environment than mouse fibroblasts, our findings showed that they undergo oxidative stress that causes CIN with age in a manner similar to mouse fibroblasts, revealing a conserved phenomenon in mammalian cells.
Longevity Relevance Analysis
(4)
The paper claims that oxidative stress leads to chromosomal instability in human fibroblasts from aged individuals. This research is relevant as it addresses a potential root cause of aging-related cellular dysfunction, specifically focusing on the mechanisms of chromosomal instability and oxidative stress in human cells, which could have implications for understanding aging and age-related diseases.
Cazzolla, G., Toppe, D., Krause, G. ...
· neuroscience
· Department of Biology, Chemistry, Pharmacy, Institute for Biology/Genetics and SupraFAB, Freie Universitaet Berlin, 14195, Berlin, Germany
· biorxiv
Macroautophagy/autophagy, a critical cellular degradation pathway essential for maintaining neuronal proteostasis, declines with age and has been increasingly implicated in the regulation of synaptic integrity and circuit resilience. Neuropeptide Y (NPY), the most abundantly expr...
Macroautophagy/autophagy, a critical cellular degradation pathway essential for maintaining neuronal proteostasis, declines with age and has been increasingly implicated in the regulation of synaptic integrity and circuit resilience. Neuropeptide Y (NPY), the most abundantly expressed neuropeptide in the mammalian brain, has emerged as a key modulator of both autophagy and aging-related processes. In Drosophila, the NPY-family peptide short Neuropeptide F (sNPF) has been shown to causally influence aging-associated changes in synaptic architecture and function, particularly at the presynaptic active zone (AZ), via non-cell autonomous mechanisms. Extending this concept to mammals, we investigated whether NPY and autophagy interact within NPY-secreting neurons to regulate age-related AZ remodeling. Our results indicate that hypothalamic NPY/AgRP neurons may exert geroprotective effects through the release of NPY and potentially other signaling molecules, thereby influencing both metabolic homeostasis and brain-wide synaptic function. These data suggest a conserved role for autophagy in maintaining presynaptic organization and resilience during aging.
Longevity Relevance Analysis
(4)
The paper claims that hypothalamic NPY/AgRP neurons influence age-related presynaptic remodeling through autophagy. This research is relevant as it explores mechanisms that may address the root causes of aging by investigating the role of autophagy and neuropeptides in maintaining synaptic integrity during aging.
Guoqiang Sun, Xiaolong Fu, Yandong Zheng ...
· Nature aging
· State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
· pubmed
Cochlear aging causes substantial hearing impairment in older adults, yet primate-specific mechanisms remain poorly characterized. Our comprehensive analysis combining single-cell and histopathological profiling in aging Macaca fascicularis demonstrates progressive cochlear degeneration featuring accelerated sensory hair cell loss, senescent spiral ganglion neurons with elevated neuroinflammation, and marked stria vascularis atrophy. We discovered that downregulation of transmembrane transport proteins, particularly SLC35F1, serves as a critical biomarker of hair cell aging. Functional validation through Slc35f1 knockdown in adult mice successfully recapitulated key aspects of age-related hearing loss, including hair cell degeneration and auditory function decline. Notably, we showed that long-term metformin administration at clinically relevant doses effectively delays cochlear aging in primates. These findings provide fundamental insights into the cellular and molecular basis of primate cochlear aging while establishing a foundation for developing targeted interventions against age-related hearing loss.
Longevity Relevance Analysis
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Downregulation of SLC35F1 is identified as a critical biomarker of hair cell aging, and metformin administration delays cochlear aging in primates. This research addresses the underlying mechanisms of cochlear aging and proposes a potential intervention, contributing to the understanding of age-related degeneration and longevity.
Alicia Toto Nienguesso, Juliane-Susanne Jung, Marie Alfes ...
· Scientific reports
· Department of Anatomy and Cell Biology, Faculty of Medicine, Martin Luther University, Halle (Saale), Germany.
· pubmed
Adipose tissue is continuously regenerated by stromal mesenchymal stem cells throughout life. This study hypothesises that early age-related changes in the proteome and metabolic properties of subcutaneous (s) and visceral (v) adipose tissue-derived stromal/stem cells (ASCs) from...
Adipose tissue is continuously regenerated by stromal mesenchymal stem cells throughout life. This study hypothesises that early age-related changes in the proteome and metabolic properties of subcutaneous (s) and visceral (v) adipose tissue-derived stromal/stem cells (ASCs) from young and old rabbits contribute to a loss of stem cell plasticity and function. To test this, the proteome and metabolic properties of ASCs from young and old rabbits were analysed using mass spectrometry-based label-free quantification and mitochondrial respiration measurements (Seahorse Mito Cell Stress Test). Both sASCs and vASCs from old rabbits exhibited comparable clusters of differentially expressed proteins. However, age-related changes were more pronounced in sASCs, suggesting that ageing affects ASCs differently depending on anatomical origin. In particular, a cluster of mitochondrial proteins in sASCs was differentially expressed with age, correlating with a shift in metabolic profile. The increase in mitochondrial respiration indicates that ageing ASCs lose their quiescent state and plasticity, leading to accelerated proliferation and differentiation. These proteomic findings were validated by Western Blot analysis, which confirmed the differential expression of key mitochondrial proteins. These results highlight the role of cellular origin in stem cell ageing and provide insights into the mechanisms underlying age-related stem cell dysfunction.
Longevity Relevance Analysis
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The study claims that age-related changes in the proteome and mitochondrial metabolism of adipose-derived stromal/stem cells contribute to a loss of stem cell plasticity and function. This research is relevant as it investigates the underlying mechanisms of stem cell aging, which is a critical aspect of understanding and potentially mitigating the effects of aging on tissue regeneration and function.
Ying Liu, Ting Hong, Mingxuan Lv ...
· Alzheimer's research & therapy
· Department of Neurology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200040, China.
· pubmed
Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy.
Emerging evidence suggests that senescent microglia play a role in β-amyloid (Aβ) pathology and neuroinflammation in Alzheimer's disease (AD). Targeting senescent cells with naturally derived compounds exhibiting minimal cytotoxicity represents a promising therapeutic strategy.
Longevity Relevance Analysis
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Delphinidin prevents microglial senescence via the AMPK/SIRT1 pathway, potentially mitigating cognitive deficits in Alzheimer's disease. The paper addresses the role of senescent cells in neurodegeneration, which is a critical aspect of aging and longevity research.
Antero Salminen, Kai Kaarniranta, Anu Kauppinen
· Biogerontology
· Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. [email protected].
· pubmed
Excessive exposure of the skin to UV radiaton (UVR) accelerates the aging process and leads to a photoaging state which involves similar pathological alterations to those occurring in chronological aging. UVR exposure, containing both UVA and UVB radiation, triggers cellular sene...
Excessive exposure of the skin to UV radiaton (UVR) accelerates the aging process and leads to a photoaging state which involves similar pathological alterations to those occurring in chronological aging. UVR exposure, containing both UVA and UVB radiation, triggers cellular senescence and a chronic inflammatory state in skin. UVR promotes oxidative stress and a leakage of double-stranded DNA (dsDNA) from nuclei and mitochondria into the cytoplasm of keratinocytes and fibroblasts. It is recognized that cytosolic dsDNA is a specific danger signal which stimulates cytoplasmic DNA sensors. The activation of the signaling through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) is a major defence and survival mechanism combatting against tissue injuries. There is abundant evidence that UVR exposure of skin stimulates cGAS-STING signaling which promotes cellular senescence and remodels both the local and systemic immune network. cGAS-STING signaling activates the IRF3 and NF-κB signaling pathways which trigger both pro-inflammatory and immunosuppressive responses. Moreover, cGAS-STING signaling stimulates inflammatory responses by activating the NLRP3 inflammasomes. Senescent fibroblasts secrete not only cytokines but also chemokines and colony-stimulating factors which induce myeloid differentiation and recruitment of immune cells into inflamed skin. Photoaging is associated with an immunosuppressive state in skin which is attributed to an expansion of immunosuppressive cells, such as Tregs. UVR-induced cGAS-STING signaling also stimulates the expression of PD-L1, a ligand for inhibitory immune checkpoint receptor, which evokes an exhaustion of effector immune cells. There is clear evidence that cGAS-STING signaling can also accelerate chronological aging by remodeling the immune network.
Longevity Relevance Analysis
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The paper claims that UV radiation-induced cGAS-STING signaling promotes cellular senescence and remodels the immune network, contributing to the aging process in skin. This research is relevant as it addresses mechanisms that underlie the aging process, specifically how UV exposure accelerates aging through immune network remodeling and cellular senescence.
Influenza A virus (IAV) infection causes acute and long-term lung damage. Here, we used immunostaining, genetic, and pharmacological approaches to determine whether IAV-induced cellular senescence causes prolonged alterations in lungs. Mice infected with a sublethal dose of H1N1p...
Influenza A virus (IAV) infection causes acute and long-term lung damage. Here, we used immunostaining, genetic, and pharmacological approaches to determine whether IAV-induced cellular senescence causes prolonged alterations in lungs. Mice infected with a sublethal dose of H1N1p2009 exhibited cellular senescence, as evidenced by increased pulmonary expression of p16, p21, β-galactosidase and the DNA damage marker gamma-H2A.X. Cellular senescence began 4 days post-infection (dpi) in the bronchial epithelium, then spread to the lung parenchyma by 7 and 28 dpi (long after viral clearance), and then declined by 90 dpi. At 28 dpi, the lungs showed severe remodeling with structural bronchial and alveolar lesions, abrasion of the airway epithelium, and pulmonary emphysema and fibrotic lesions that persisted up to 90 dpi. In mice and nonhuman primates, persistence of senescent cells in the bronchial wall on 28 dpi was associated with abrasion of the airway epithelium. In p16-ATTAC mice, depletion of p16-expressing cells with AP20187 reduced pulmonary emphysema and fibrosis and led to complete recovery of the airway epithelium at 28 dpi, indicating a marked acceleration of the epithelial repair process. Treatment with the senolytic drug ABT-263 also accelerated epithelial repair without affecting pulmonary fibrosis or emphysema. These positive effects occurred independently of viral clearance and lung inflammation at 7 dpi. Finally, AP20187 treatment of p16-ATTAC mice at 15 dpi led to complete recovery of the airway epithelium at 28 dpi. Thus, virus-induced senescent cells contribute to the pulmonary sequelae of influenza; targeting senescent cells may represent a new preventive therapeutic option.
Longevity Relevance Analysis
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Virus-induced cellular senescence contributes to long-term pulmonary damage post-influenza infection, and targeting these senescent cells may offer a therapeutic strategy. The study addresses the role of cellular senescence, a key mechanism associated with aging, in the context of viral infection and its long-term effects, which is relevant to understanding and potentially mitigating age-related decline.