Seung Hyuk T Lee, Asha Kar, Kyla Z Gelev ...
· Nature communications
· Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
· pubmed
Obesity impairs subcutaneous adipose tissue function, which predisposes to chronic cardiometabolic comorbidities and accelerated biological aging. However, regulatory variants, their target genes and epigenomic landscape underlying this predisposition in each subcutaneous adipose...
Obesity impairs subcutaneous adipose tissue function, which predisposes to chronic cardiometabolic comorbidities and accelerated biological aging. However, regulatory variants, their target genes and epigenomic landscape underlying this predisposition in each subcutaneous adipose tissue cell-type remain elusive. Our subcutaneous adipose tissue cell-type level cis-expression quantitative trait and colocalization analyses reveal cis-expression quantitative trait locus variants, regulating 279 genes for 33 cardiometabolic disease and aging traits. Most of these genes are cell-type-specific (90%), led by adipocytes (55%), and missed in previous bulk tissue colocalization studies. Conducting subcutaneous adipose tissue cell-type level epigenome analysis, we discover that the vast majority (81%) of these colocalized cardiometabolic disease and aging risk variants map to the active chromatin compartments that comprise only 45% of the human genome, revealing three-dimensional epigenome in the center of cardiometabolic disease and aging risk. These findings uncover genetic and epigenomic regulation of genes underlying 33 cardiometabolic disease and aging traits in subcutaneous adipose tissue cell-types and offer critical insights into the principal role of three-dimensional chromatin in disease risk.
Longevity Relevance Analysis
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The paper claims that specific genetic and epigenomic factors in subcutaneous adipose tissue are linked to cardiometabolic diseases and aging traits. This research is relevant as it explores the underlying genetic and epigenomic mechanisms that contribute to aging and age-related diseases, potentially addressing root causes rather than just symptoms.
Piotr Paweł Chmielewski
· Biogerontology
· Division of Anatomy, Department of Human Morphology and Embryology, Faculty of Medicine, Wroclaw Medical University, 6a Chałubińskiego Street, 50-368, Wrocław, Poland. piotr.chmielewski@umw.edu.pl.
· pubmed
Biological ageing is often approached through its underlying mechanisms and their therapeutic potential. Yet age-related decline arises from multiple processes shaped by evolutionary constraints and finite investment in somatic maintenance. Coupling among these processes is heter...
Biological ageing is often approached through its underlying mechanisms and their therapeutic potential. Yet age-related decline arises from multiple processes shaped by evolutionary constraints and finite investment in somatic maintenance. Coupling among these processes is heterogeneous: some are tightly linked through shared signalling networks, others are indirectly related and some retain substantial autonomy. Interventions that modulate biomarkers of biological age or individual hallmarks typically produce partial, tissue-selective effects rather than uniform reversal of ageing in humans. This pattern is more consistent with a distributed network of partially independent processes with key nodes of regulatory integration than with a single upstream mechanism. Because molecular, cellular, tissue and organismal levels retain partial autonomy, human ageing can be viewed as a multilevel phenomenon. Geroscience may therefore advance by mapping this network and identifying interventions that target central regulatory hubs and affect multiple downstream processes, thereby preserving function, extending healthspan and reducing the burden of ageing.
Longevity Relevance Analysis
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The paper claims that human ageing is a multilevel phenomenon influenced by a network of partially independent processes. This is relevant as it addresses the root causes of aging and suggests a framework for interventions that could extend healthspan and reduce age-related decline.
Pingjing Zheng, Wendi Yan, Yangnan Ding ...
· Cardiovascular Diseases
· Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.
· pubmed
Cardiovascular disease (CVD) predominantly affects elderly individuals and is the leading cause of morbidity, disability, and mortality worldwide. Systemic ageing, especially cardiovascular ageing, contributes to the development of CVD phenotypes and outcomes. Therefore, in this ...
Cardiovascular disease (CVD) predominantly affects elderly individuals and is the leading cause of morbidity, disability, and mortality worldwide. Systemic ageing, especially cardiovascular ageing, contributes to the development of CVD phenotypes and outcomes. Therefore, in this review, we innovatively summarize the five major etiologies and risk factors for cardiovascular ageing, including lifestyle and behavioral factors, metabolic disorders and physiological dysregulation, environmental exposures and physicochemical determinants, genetics and epigenetics, and host biology and sociodemographic determinants. Furthermore, we enumerate the structural and functional changes that occur in the cardiovascular ageing process. The twelve hallmarks of cardiovascular ageing, including genomic instability and epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, oxidative stress, and inflammation; cellular dysfunction; cellular senescence; stem cell exhaustion; metabolic changes; and the renin‒angiotensin‒aldosterone system, β-adrenergic signaling, growth signaling, and mechanosignaling, stratify across three dimensions: molecular, cellular, and systemic levels. Given the elucidated role of cardiovascular ageing in diverse pathologies, we propose specific rejuvenation strategies to mitigate residual cardiovascular risk in older adults: targeting senescent cells, adjusting energy sensor pathways, addressing central inflammatory pathways, modulating neurocardiological dynamics, adopting healthy lifestyles, and assessing and preventing the degree of ageing. We also list FDA-approved drugs and clinical trials targeting cardiovascular ageing, thus serving as a cutting-edge reference for developing intervention strategies.
Longevity Relevance Analysis
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The paper proposes rejuvenation strategies to mitigate cardiovascular ageing and its associated risks in older adults. This research addresses the underlying mechanisms of cardiovascular ageing, which is crucial for developing interventions that could potentially extend healthspan and lifespan.
Zhongshen Li, Jixiang Yu, Shen You ...
· IEEE journal of biomedical and health informatics
· Not available
· pubmed
Geroprotectors underpin therapeutic strategies to intervene in aging pathologies and extend lifespans. Unfortunately, geroprotector discovery remains a significant challenge due to data quality and pathway redundancy. Existing methods often rely on single data modalities, which f...
Geroprotectors underpin therapeutic strategies to intervene in aging pathologies and extend lifespans. Unfortunately, geroprotector discovery remains a significant challenge due to data quality and pathway redundancy. Existing methods often rely on single data modalities, which fail in capturing the intricate structure-activity relationships in geroprotector molecules. Therefore, we present Gero-LLM, a multimodal framework that synergizes the reasoning capabilities of pre-trained large language models (LLMs) with the topological modeling of Graph Isomorphism Network with Edge features (GINE) for geroprotector discovery. By fusing textual representations with structural embeddings, Gero-LLM leverages multimodal chemical information to enhance predictive ability. To overcome the limitations of standard fine-tuning, we utilize a cross-modal differentiated deep mutual learning (CM-Diff-DML) strategy. This training paradigm enforces the diversity between modalities, preventing mode collapse and improving model prediction ability. Gero-LLM achieves state-of-the-art performance, demonstrating promising robustness on highly imbalanced external datasets, resembling the real-world geroprotector screening scenarios. Furthermore, in silico mutagenesis confirms that Gero-LLM captures fundamental chemical pharmacophores beyond summary statistics. This work attempts to bridge the gaps between LLMs and multimodal molecule information, providing a robust platform to accelerate the discovery of therapeutic interventions on aging.
Longevity Relevance Analysis
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Gero-LLM proposes a multimodal framework for discovering geroprotectors that can potentially intervene in aging processes. The paper is relevant as it addresses the discovery of therapeutic interventions aimed at the root causes of aging rather than merely treating age-related symptoms.
Mitchell E Fane, Daniel J Zabransky
· Cancer research
· Fox Chase Institute for Cancer Research Philadelphia, Pa United States.
· pubmed
Aging is a major risk factor for cancer incidence and mortality, but its effect on tumor evolution and metastatic progression remains incompletely understood. A recent study by Patel and colleagues published in Nature reveals a paradoxical role for aging in cancer biology: while ...
Aging is a major risk factor for cancer incidence and mortality, but its effect on tumor evolution and metastatic progression remains incompletely understood. A recent study by Patel and colleagues published in Nature reveals a paradoxical role for aging in cancer biology: while aging constrains primary tumor growth, it simultaneously enhances metastatic spread. Using genetically engineered mouse models and patient-derived data, the authors demonstrate that aging epigenetically reprograms mutant KRAS-driven lung adenocarcinoma through activation of the integrated stress response (ISR). Central to this process is the transcription factor ATF4, which promotes epithelial plasticity and metabolic adaptations, thereby enabling metastasis. This work provides a mechanistic framework linking host aging to tumor cell state transitions that favor distant spread of cancer cells. Importantly, it challenges a long-held assumption that tumor aggressiveness is primarily reflected by primary tumor growth kinetics and properties, and instead, it highlights metastasis as a distinct, age-influenced evolutionary trajectory. The identification of ATF4-driven ISR signaling as a mediator of metastasis highlights new therapeutic vulnerabilities, such as an acquired dependence on glutamine, particularly for older patients who comprise the majority of lung cancer cases. More broadly, this study underscores the need to incorporate aging biology into cancer models and therapeutic strategies, redefining how we conceptualize tumor progression across the lifespan.
Longevity Relevance Analysis
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Aging enhances metastatic spread of cancer through the activation of the integrated stress response mediated by ATF4. This paper is relevant as it explores the mechanistic link between aging and cancer progression, addressing how aging influences tumor evolution and suggesting potential therapeutic strategies that could target age-related vulnerabilities in cancer treatment.
Wenxin Qi, Qian Liu, Naijun Dong ...
· Ferroptosis
· School of Life Sciences, Shanghai University, Shanghai, China.
· pubmed
Brain aging is accompanied by cognitive decline and an increased risk of neurodegenerative disease, with neuronal aging being a key causative factor. Studies have shown that the earliest damage to blood-brain barrier (BBB) integrity occurs in the hippocampus, leading to the abnor...
Brain aging is accompanied by cognitive decline and an increased risk of neurodegenerative disease, with neuronal aging being a key causative factor. Studies have shown that the earliest damage to blood-brain barrier (BBB) integrity occurs in the hippocampus, leading to the abnormal accumulation of Fe²⁺;however, the mechanisms underlying subsequent neuronal aging remain unclear. Using single-cell and spatial transcriptomic analyses, this study focuses on the phospholipid flippase ATP11B. We found that ATP11B deficiency facilitates the transport of Fe²⁺ from ependymal cells to hippocampal neurons, activating the Hippo signaling pathway and inducing mitochondrial respiratory dysfunction and dynamic imbalance, which results in neuronal ferroptosis and exacerbation of aging phenotypes. Mechanistically, ATP11B blocks mitochondrial respiratory function by regulating the chromatin accessibility of KLF4 to mitochondrial respiratory chain complex genes. Simultaneously, it impairs the mitochondrial quality control system, resulting in elevated levels of reactive oxygen species(ROS) and enhanced neuronal aging. The mitochondria-associated metabolite, lactate, facilitates histone lactylation of ferroptosis and the key aging-related genes Acsl4, Trp53 and Cdkn1a via the TEAD-YAP complex, thereby promoting transcription. This research uncovers the molecular mechanism through which ATP11B mediates neuronal aging: regulating the iron transport-mitochondrial plasticity axis. This provides a novel avenue for targeting iron homeostasis to intervene in cognitive decline and neurodegenerative disease.
Longevity Relevance Analysis
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The paper claims that targeting the ATP11B-YAP axis can repair mitochondrial function and inhibit neuronal ferroptosis, thereby attenuating age-related cognitive decline. This research addresses the underlying mechanisms of neuronal aging and cognitive decline, focusing on iron transport and mitochondrial function, which are critical factors in the aging process.
Tetiana Poliezhaieva, Yuting Li, Prerana Shrikant Chaudhari ...
· Nature communications
· Leibniz Institute on Aging - Fritz Lipmann Institute (FLI), Beutenbergstrasse 11, Jena, Germany.
· pubmed
Mitochondrial dysfunction is a prominent hallmark of aging contributing to the decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here...
Mitochondrial dysfunction is a prominent hallmark of aging contributing to the decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we use proteomics, lipidomics, genetics and functional tests in wild type Caenorhabditis elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that support longevity amid persistent mitochondrial inefficiency. These tests and subsequent transcriptomics and metabolomics analyses in humans reveal aging-associated decline of phosphatidylcholine synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, ectopic boosting of phosphatidylcholine levels via diet restores late life mitochondrial integrity in vivo in nematodes and reinstates metabolic resilience in human cell culture tests. We thus describe a previously unrecognized natural driver of mitochondrial decline in aging that is malleable by dietary interventions.
Longevity Relevance Analysis
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The paper claims that the decline of phosphatidylcholine synthesis is a trigger of mitochondrial dysfunction during aging, which can be mitigated by dietary interventions. This research addresses a potential root cause of mitochondrial aging and suggests a malleable intervention, aligning with longevity research goals.
Anderton, E., Burton, J. B., King, C. D. K. D. ...
· cell biology
· Buck Institute for Research on Aging
· biorxiv
Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Here, using detergen...
Loss of proteostasis and the accumulation of insoluble protein aggregates are features of aging across model organisms and occur in all major age-related neurodegenerative diseases; yet how aggregation proceeds during normal human brain aging remains unknown. Here, using detergent-fractionation proteomics, we show that brain aging does not involve uniform aggregate accumulation; rather, the insoluble proteome undergoes asymmetric remodeling beginning in midlife, with maximum-stability aggregates declining sharply by old age and intermediate-stability aggregates accumulating progressively before accelerating after age 80. Intermediate-stability aggregates are prone to liquid-liquid phase separation and are enriched among Alzheimer's disease plaque and tangle constituents. Proteasome and cytosolic chaperone capacity predict individual differences in aggregate burden as strongly as chronological age, offering human-level evidence in support of therapies targeting these pathways. These findings establish aggregate remodeling as a feature of normal brain aging and position intermediate-stability aggregate accumulation as a molecular event on the path to neurodegenerative disease.
Longevity Relevance Analysis
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The paper claims that intermediate-stability protein aggregates accumulate during normal brain aging and are linked to neurodegenerative disease progression. This research is relevant as it addresses the mechanisms of proteostasis decline in aging, which is a fundamental aspect of the aging process and its associated diseases.
Eunhwan Kim, Jae Sook Kang, Yong Ryoul Yang
· Experimental & molecular medicine
· Aging Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, Republic of Korea.
· pubmed
Aging arises not only from intrinsic cellular decline but also from systemic alterations in circulating factors that govern tissue maintenance and regeneration. Recent multi-omics advances - including plasma proteomics, metabolomics, and single-cell immunomics - highlight blood a...
Aging arises not only from intrinsic cellular decline but also from systemic alterations in circulating factors that govern tissue maintenance and regeneration. Recent multi-omics advances - including plasma proteomics, metabolomics, and single-cell immunomics - highlight blood as both a mirror and a modulator of organismal aging. Circulating proteins and metabolites reflect not only chronological and biological age but also organ-specific aging trajectories, serving as robust predictors of healthspan, longevity, and disease risk. Beyond their diagnostic value, blood-borne components actively dictate the tempo of aging by shaping immune remodeling, metabolic homeostasis, and interorgan communication. Youthful circulation, defined as the blood-borne systemic environment of young individuals, promotes tissue homeostasis and regeneration and, when experimentally transferred via heterochronic parabiosis or young plasma transfer, induces transcriptomic, metabolic, and epigenetic rejuvenation across multiple tissues. Specific fractions - such as small extracellular vesicles, plasma proteins, and metabolites - restore mitochondrial function, suppress inflammation, and extend lifespan in animal models. Conversely, reducing pro-aging factors through plasma dilution or therapeutic plasma exchange mitigates age-associated decline and shows translational promise in neurodegenerative disease. Collectively, these insights position blood as a central regulatory axis of aging. In this Review, we synthesize current mechanistic and translational evidence on blood-borne aging regulators to outline a molecular framework for rejuvenation biology and future therapeutic development.
Longevity Relevance Analysis
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Blood-borne components actively dictate the tempo of aging and can induce rejuvenation across multiple tissues. The paper is relevant as it explores systemic factors in blood that influence aging and longevity, focusing on mechanisms that could lead to therapeutic interventions targeting the root causes of aging rather than merely addressing age-related diseases.
Fahed, G., Cauwenberghs, N., Santana, E. J. ...
· cardiovascular medicine
· Stanford University
· medrxiv
Background: Among cardiac measures, diastolic parameters demonstrate the earliest and most consistent age-related changes. This can be leveraged to develop a continuous left ventricular (LV) Diastolic Age from routine echocardiographic parameters. Analogous to how epigenetic cloc...
Background: Among cardiac measures, diastolic parameters demonstrate the earliest and most consistent age-related changes. This can be leveraged to develop a continuous left ventricular (LV) Diastolic Age from routine echocardiographic parameters. Analogous to how epigenetic clocks weight molecular markers against mortality risk, we calibrated Diastolic Age by weighting echocardiographic features against the validated PREVENT-Heart Failure (HF) risk score. Methods: We analyzed 1,952 participants from the Project Baseline Health Study (median age 50 [36-64] years, 54% female). The measure was derived using partial least-squares regression anchored on PREVENT-HF and calibrated within a healthy reference subgroup. External validation was performed in the WASE (n=1,708) and Stanford Cardiovascular Aging (n=313) cohorts. Associations with ASE-defined LV diastolic dysfunction (LVDD), epigenetic clocks, and major adverse cardiovascular events (MACE) were examined. Results: Diastolic Age correlated strongly with chronological age (r=0.78) with robust external validation (WASE r=0.76; Stanford r=0.82; calibration slopes {approx}1.0). It increased progressively across grades of diastolic dysfunction and discriminated LVDD with an AUC of 0.89 (95% CI 0.87-0.92), and was independently associated with hypertension, diabetes, and elevated C-reactive protein. While correlated with the Levine (r=0.76) and Horvath (r=0.41) epigenetic clocks, residual analyses indicated that Diastolic Age captures a distinct cardiac-specific dimension of biological aging. Over median follow-up of 4.2 years, it independently predicted MACE (HR 2.30, 95% CI 1.70-3.18), with accelerated diastolic aging across all age groups among those with events. Discrimination was comparable to ASE-defined LVDD (C-index 0.83 vs. 0.82). Conclusion: Diastolic Age provides a continuous, echocardiography-derived measure of cardiac biological aging that complements categorical diastolic grading and epigenetic aging clocks, and independently predicts cardiovascular outcomes.
Longevity Relevance Analysis
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Diastolic Age is a continuous measure of cardiac biological aging that predicts major adverse cardiovascular events. The paper is relevant as it addresses a novel approach to quantifying biological aging in the heart, which could have implications for understanding and potentially mitigating age-related cardiovascular diseases.
Shen, Y., Li, J., Wang, S. ...
· cell biology
· Shanghai Institute of Biochemistry and Cell Biology, CAS
· biorxiv
Intraflagellar transport (IFT) is essential for cilia, and its dysfunction drives ciliopathies and systemic ageing. However, the in vivo dynamics of individual components in the IFT complexes remain obscured, leaving the mechanisms of age-dependent IFT failure largely unknown. He...
Intraflagellar transport (IFT) is essential for cilia, and its dysfunction drives ciliopathies and systemic ageing. However, the in vivo dynamics of individual components in the IFT complexes remain obscured, leaving the mechanisms of age-dependent IFT failure largely unknown. Here, we report a dual-color super-resolution imaging strategy to dissect the structural integrity and kinetics of IFT trains in the sensory cilia of young and aged Caenorhabditis elegans. We show that IFT complexes are not static entities. Instead, distinct components undergo dynamic dissociation within IFT trains. This intra-complex dissociation causes a remarkable reduction in IFT velocity and is significantly exacerbated in the cilia of aged worms. Mechanistically, we identify the conserved TRiC/CCT chaperonin complex and daf-19/RFX, the master transcription factor driving IFT genes, as critical regulators of IFT stability. We demonstrate that their age-dependent downregulation drives the progressive IFT component dissociation. Our findings re-frame the IFT complex as a highly dynamic assembly, uncover a new dimension of IFT regulation, and identify the progressive uncoupling of IFT components as a key driver of ciliary dysfunction during ageing.
Longevity Relevance Analysis
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The paper claims that age-dependent downregulation of specific regulators leads to dynamic dissociation of IFT components, driving ciliary dysfunction during aging. This research is relevant as it addresses the mechanisms of age-related decline in ciliary function, which is linked to broader aging processes and potential interventions in longevity.
Jia-Jun Zhao, Ming Hu, Siyan Li ...
· Nature communications
· State Key Laboratory for Development and Utilization of Forest Food Resources, College of Food and Health, Zhejiang A&F University, Hangzhou, Zhejiang, China.
· pubmed
Identifying robust, non-invasive biomarkers of biological age is key to preventive medicine. While gut aging clocks exist, the oral microbiome remains underexplored as a quantitative biomarker. Using oral microbiome data from two NHANES cohorts (N = 4,675), we identified 64 age-d...
Identifying robust, non-invasive biomarkers of biological age is key to preventive medicine. While gut aging clocks exist, the oral microbiome remains underexplored as a quantitative biomarker. Using oral microbiome data from two NHANES cohorts (N = 4,675), we identified 64 age-dependent bacterial genera and developed a machine learning model predicting chronological age, with generalizability in an independent external cohort (N = 1,293). We derived an Oral Microbiome Aging Acceleration (OMAA) Score as the residual of predicted age against chronological age. The OMAA Score independently predicted all-cause mortality (HR = 1.05, P = 0.024) and frailty (OR = 1.05, P = 0.008), correlated with impaired kidney function (lower eGFR: β = -0.066, P = 5.22×10
Longevity Relevance Analysis
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The paper claims that oral microbiome signatures can predict biological age and host health outcomes. This research is relevant as it explores the oral microbiome as a potential biomarker for biological aging, which could contribute to understanding and addressing the root causes of aging and age-related health issues.
Hiraki-Kamon, K., Wada, A., Suyama, T. ...
· cell biology
· Ehime university
· biorxiv
Mesenchymal stem cell (MSC) heterogeneity and conventional phenotypic criteria limitations represent major bottlenecks in therapeutic manufacturing. Here, we present a framework to prospectively identify naturally superior MSCs by shifting from superficial markers to the digital ...
Mesenchymal stem cell (MSC) heterogeneity and conventional phenotypic criteria limitations represent major bottlenecks in therapeutic manufacturing. Here, we present a framework to prospectively identify naturally superior MSCs by shifting from superficial markers to the digital quantification of fundamental epigenetic flaws in inferior clones. We show that intrinsic MSC functional decline is driven by targeted hypermethylation of poised enhancers, causing paradoxical derepression of developmental genes. We term this process poised enhancer decommissioning (PEnD). By isolating this universal decay axis from donor-specific immunological variability, we translate this complex epigenetic state into a streamlined transcriptomic signature: the Poised Enhancer-related Gene Expression (PErGE) score. Overcoming the limitations of standard in vitro differentiation assays, our approach enables accurate, donor-independent prediction of long-term proliferative potential. Together, our findings establish a mechanism-based biomarker of cellular aging, and provide a readily applicable tool to improve the quality control of next-generation MSC-based therapies.
Longevity Relevance Analysis
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The paper claims to establish a mechanism-based biomarker of cellular aging through the identification of poised enhancer decommissioning in mesenchymal stem cells. This research is relevant as it addresses intrinsic mechanisms of cellular aging and proposes a framework that could enhance the quality of stem cell therapies, potentially impacting longevity and age-related therapeutic strategies.
Xiaoman Wang, Shen-Shen Cui, Xun-Kai Li ...
· Nature metabolism
· State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences & School of Basic Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
· pubmed
Ageing leads to diurnal misalignment with a global reduction in physiological fitness, yet the mechanisms underlying such age-related diurnal reprogramming and its role in ageing remain poorly understood. Here we generate diurnal transcriptomes across eight peripheral tissues and...
Ageing leads to diurnal misalignment with a global reduction in physiological fitness, yet the mechanisms underlying such age-related diurnal reprogramming and its role in ageing remain poorly understood. Here we generate diurnal transcriptomes across eight peripheral tissues and reveal that disrupted redox oscillations are common diurnal alterations in organismal ageing. Restoring redox rhythms through the time-restricted application of antioxidants and pro-oxidants markedly improved glucose metabolism, motor performance and ageing-related characteristics of liver and skeletal muscle in male aged mice. Through multi-omics analyses we further reveal that restoring redox rhythms partially rejuvenates the hepatic transcriptome and chromatin accessibility in ageing-associated functional pathways and involves redox modification of CLOCK protein. Perturbing redox-sensitive cysteine 195 of CLOCK causes premature ageing phenotypes and hepatic reprogramming. Overall, our study reveals that redox rhythms ameliorate functional decline by modulating ageing-relevant reprogramming in liver and skeletal muscle and indicates that redox rhythm-based interventions might promote healthy ageing.
Longevity Relevance Analysis
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Restoring redox rhythms can improve physiological fitness and modulate ageing-related reprogramming in aged mice. The study addresses mechanisms underlying ageing and proposes interventions that may promote healthy ageing, aligning with the goal of understanding and potentially mitigating the root causes of aging.
Kai Gai, Wenjian Li, Junpeng Li ...
· npj aging
· Institute of Rare Diseases, West China Hospital of Sichuan University, Chengdu, China.
· pubmed
Biological aging is a complex process associated with declining physiological function and increased risk of aging-related diseases. However, its risk factors and molecular mechanisms remain poorly understood. Here, we performed a comprehensive integrative analysis to identify pu...
Biological aging is a complex process associated with declining physiological function and increased risk of aging-related diseases. However, its risk factors and molecular mechanisms remain poorly understood. Here, we performed a comprehensive integrative analysis to identify putative risk factors and molecular phenotypes associated with four epigenetic aging acceleration and human longevity. We first investigated the association between aging-related traits and potential risk factors using genome-wide association study (GWAS) data, identifying cholesterol levels, immune cell traits and insulin-like growth factor-1 (IGF1) as associated with longevity. To investigate the molecular mechanisms, we integrated GWAS summary data for epigenetic aging and longevity with five types of molecular QTL (xQTL) datasets, including gene expression (eQTL), splicing (sQTL), alternative polyadenylation (apaQTL), protein (pQTL), and metabolite QTL (mQTL). We identified 30 genes, 11 splicing events, 5 proteins, 3 alternative polyadenylation events, and 39 metabolites associated with aging-related traits, highlighting key regulatory mechanisms that link genetic variants to epigenetic aging and longevity. Drug-target annotation using DrugBank further prioritized therapeutic candidates, including CASP8, PSRC1 and SORT, as potential intervention targets. These findings provide a comprehensive resource for understanding the molecular architecture of aging and highlight potential novel targets for precision interventions in aging-related diseases.
Longevity Relevance Analysis
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The paper identifies genetic and molecular factors associated with human longevity and epigenetic aging. This research is relevant as it explores the underlying mechanisms of aging and potential interventions, contributing to the understanding of longevity beyond merely treating age-related diseases.
An, J., Hu, X., Jiang, Y. ...
· bioinformatics
· Peking University
· biorxiv
The human brain varies across anatomical regions, cell types, development, ageing and disease states, yet existing single-cell transcriptomic resources remain fragmented and difficult to integrate into a unified biological model. Here we present DigitalBrain, a human brain-specif...
The human brain varies across anatomical regions, cell types, development, ageing and disease states, yet existing single-cell transcriptomic resources remain fragmented and difficult to integrate into a unified biological model. Here we present DigitalBrain, a human brain-specific atlas and foundation-model framework for organizing diverse and fragmented human brain transcriptomic data across scales. We first built DigitalBrain-Atlas, a harmonized whole-brain single-cell resource comprising 16.35 million transcriptomes from 2,143 donors across 165 brain regions, spanning the human lifespan and multiple neurological and clinical conditions. We then developed DigitalBrain-M1, a Transformer-based model that jointly encodes gene identity and expression magnitude to learn a shared embedding space for cells and genes. Across held-out datasets, DigitalBrain supported robust single-cell integration, clustering and cell-type annotation while preserving major biological structure and reducing technical fragmentation. Beyond these benchmarks, the learned embeddings revealed emergent large-scale hierarchical organization of the human brain, linking anatomically distinct regions into higher-order patterns consistent with known functional systems. Applied to human hippocampal aging, DigitalBrain identified cell-type-specific aging sensitive gene sets, identified dentate gyrus granule cells as a particularly age-sensitive population, and discovered selective reorganization of gene programs related to synaptic transmission, postsynaptic structure, membrane excitability and axon guidance during aging. Cross-dataset convergence was strongest at the level of functional modules and recurrent aging sensitive genes. Together, these results demonstrate DigitalBrain as a brain-specific framework for mapping human brain organization across scales, and as an early step towards a complete virtual organ for the human brain.
Longevity Relevance Analysis
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DigitalBrain provides a framework for understanding the transcriptomic organization of the human brain, revealing age-sensitive gene sets related to hippocampal aging. The paper is relevant as it addresses cellular and molecular changes associated with aging, contributing to the understanding of the biological mechanisms underlying age-related changes in the brain.
Ivan A Salladay-Perez, Itzetl Avila, Lizeth Estrada ...
· Nature aging
· Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
· pubmed
Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether ma...
Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.
Longevity Relevance Analysis
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The paper identifies p21⁺Trem2⁺ senescent macrophages as a significant contributor to chronic inflammation in aging and metabolic liver disease, suggesting a potential therapeutic target for addressing root causes of aging-related inflammation. This research is relevant as it explores cellular senescence mechanisms that drive aging-related diseases, contributing to the understanding of aging processes and potential interventions.
Zhang, B., Hsiung, K. C., Biju, R. ...
· genetics
· University College London
· biorxiv
Reduced insulin/IGF-1 signaling (IIS) can greatly extend lifespan in C. elegans. However, its effects on the duration of healthy life (healthspan) remain unclear, with several reports of either morbidity expansion or scaled effects, though none of morbidity compression. Moreover,...
Reduced insulin/IGF-1 signaling (IIS) can greatly extend lifespan in C. elegans. However, its effects on the duration of healthy life (healthspan) remain unclear, with several reports of either morbidity expansion or scaled effects, though none of morbidity compression. Moreover, life-extension by IIS reduction is particularly inter-individually variable within populations, confounding efforts to understand the intra-individual biology of such interventions. Here, we performed a longitudinal investigation at individual nematode resolution, of IIS reduction on aging-related health and lifespan, through temporally-controlled auxin-induced degradation (AID) of the DAF-2 insulin/IGF-1 receptor. Our results show how inter-individual variation in aging rate within control populations explains the complex demographic effects of age-specific DAF-2 AID on population lifespan. Strikingly, adult-limited IIS reduction causes an inter-individually homogeneous increase in lifespan (reducing Gompertz rather than {beta}) that is driven by healthspan expansion and compression of morbidity. Unexpectedly, cessation of DAF-2 AID in decrepit elderly individuals rejuvenates locomotory capacity and extends lifespan, showing that higher levels of IIS are optimal for health and survival towards the end of life. We also document a memory effect of transient IIS reduction during early adulthood, that is sufficient to fully extend lifespan (+189% median lifespan). Together, these findings demonstrate that both lifespan and healthspan can be maximized by appropriate temporal and directional modulation of IIS.
Longevity Relevance Analysis
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The paper claims that appropriate temporal modulation of insulin/IGF-1 signaling can maximize both lifespan and healthspan. This research is relevant as it explores the mechanisms underlying aging and healthspan extension, addressing the root causes of aging rather than merely treating age-related symptoms.
Tea Shavlakadze, Kun Xiong, Romain Donne ...
· Aging
· Regeneron Pharmaceuticals, 777 Old Saw Mill River Road, Tarrytown, NY 10591 USA.
· pubmed
To determine the genes and pathways that are up- or down-regulated in a consistent manner throughout the rodent lifespan, we generated a high N age-related gene expression atlas in mice and rats, by profiling 28 tissues in male and female C57BL/6J mice and 32 tissues in male Spra...
To determine the genes and pathways that are up- or down-regulated in a consistent manner throughout the rodent lifespan, we generated a high N age-related gene expression atlas in mice and rats, by profiling 28 tissues in male and female C57BL/6J mice and 32 tissues in male Sprague Dawley rats (>5000 samples) over multiple time points. We identified age-related genes and pathways that change either early in life, at mid-age, late in life, or linearly throughout the animals' lifespan. Linear genes dominated many but not all tissues, and certain tissues were relatively spared from age-related changes. We explored common and different features of aging between tissues, sexes, and species. Given the expanse of our transcriptomic dataset, we believe that this study will serve as a useful resource for understanding the timing, tissue specificity, sex-specificity, and species specificity of age-related gene and pathway changes in mice and rats.
Longevity Relevance Analysis
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The paper claims to identify age-related genes and pathways that change consistently throughout the rodent lifespan. This research is relevant as it aims to elucidate the biological mechanisms of aging, which could contribute to understanding the root causes of aging and inform potential interventions for lifespan extension.