Yishu Wang, Jianmei Huang, Sixiong Lin ...
· Bone research
· Department of Biochemistry, Homeostatic Medicine Institute School of Medicine Shenzhen Key Laboratory of Cell Microenvironment, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Southern University of Science and Technology, Shenzhen, China.
· pubmed
The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-relate...
The focal adhesion (FA) is the structural basis of the cell-extracellular matrix crosstalk and plays important roles in control of organ formation and function. Here we show that expression of FA protein vinculin is dramatically reduced in osteocytes in patients with aging-related osteoporosis. Vinculin loss severely impaired osteocyte adhesion and dendrite formation. Deleting vinculin using the mouse 10-kb Dmp1-Cre transgenic mice causes dramatic bone loss in the weight-bearing long bones and spine, but not in the skull, in both young and aged mice by impairing osteoblast formation and function without markedly affecting bone resorption. Vinculin loss impairs the anabolic response of skeleton to mechanical loading in mice. Vinculin knockdown increases, while vinculin overexpression decreases, sclerostin expression in osteocytes without impacting expression of Mef2c, a major transcriptional regulator of the Sost gene, which encodes sclerostin. Vinculin interacts with Mef2c and retains the latter in the cytoplasm. Thus, vinculin loss enhances Mef2c nuclear translocation and binding to the Sost enhancer ECR5 to promote sclerostin expression in osteocytes and reduces bone formation. Consistent with this notion, deleting Sost expression in osteocytes reverses the osteopenic phenotypes caused by vinculin loss in mice. Finally, we find that estrogen is a novel regulator of vinculin expression in osteocytes and that vinculin-deficient mice are resistant to ovariectomy-induced bone loss. Thus, we demonstrate a novel mechanism through which vinculin inhibits the Mef2c-driven sclerostin expression in osteocytes to promote bone formation.
Longevity Relevance Analysis
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The paper claims that vinculin regulates sclerostin expression in osteocytes, influencing bone formation and mass. This research is relevant as it addresses mechanisms underlying bone loss associated with aging, potentially offering insights into interventions that could mitigate age-related osteoporosis.
Haruhisa Kawasaki, Toshihiko Sato, Norio Ishida
· Biogerontology
· Institute for Chronobiology, Foundation for Advancement of International Science (FAIS), 3-24-16 Kasuga, Tsukuba, Ibaraki, 305-0812, Japan.
· pubmed
Cannabidiol (CBD), a non-psychoactive cannabinoid, has been studied for its various health-promoting effects recently. This study investigates the effects of dietary CBD to the circadian clock of Drosophila melanogaster as a model animal and its many physiological effect to flies...
Cannabidiol (CBD), a non-psychoactive cannabinoid, has been studied for its various health-promoting effects recently. This study investigates the effects of dietary CBD to the circadian clock of Drosophila melanogaster as a model animal and its many physiological effect to flies. We showed that CBD extended the period of locomotor activity in a dose-dependent manner, suggesting its influence on the circadian clock. Additionally, CBD improved sleep quality and extended lifespan under starvation conditions. The study also revealed enhanced rhythmicity in Close Proximity (CP) rhythm and increased eggs reproduction with dietary CBD supplementation. Furthermor, CBD attenuates age-related motor dysfunction in wild-type and Parkinson's disease (PD) model in Drosophila. These findings strongly suggest that appropriate amount of CBD affects the circadian rhythms, sleep, life span, CP rhythm, egg reproduction and motor function of Drosophila melanogaster, and providing a basic data for exploring its potential applications in managing circadian-related disorders in other animals.
Longevity Relevance Analysis
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Cannabidiol (CBD) extends lifespan and improves various physiological functions in Drosophila melanogaster. The study investigates the effects of CBD on circadian rhythms and lifespan, which are directly related to aging and longevity research.
Emily R Lowry, Tulsi Patel, Jonathon A Costa ...
· Nature neuroscience
· Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY, USA. [email protected].
· pubmed
Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resi...
Aging is a major risk factor in amyotrophic lateral sclerosis (ALS) and other adult-onset neurodegenerative disorders. Whereas young neurons are capable of buffering disease-causing stresses, mature neurons lose this ability and degenerate over time. We hypothesized that the resilience of young motor neurons could be restored by reexpression of the embryonic motor neuron selector transcription factors ISL1 and LHX3. We found that viral reexpression of ISL1 and LHX3 selectively in postnatal motor neurons reactivates aspects of their youthful gene expression program and alleviates key disease-relevant phenotypes in the SOD1
Longevity Relevance Analysis
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The paper claims that reexpression of embryonic motor neuron factors ISL1 and LHX3 in postnatal motor neurons can reactivate youthful gene expression and alleviate ALS symptoms. This research is relevant as it explores mechanisms to restore youthful characteristics in neurons, potentially addressing the underlying causes of neurodegeneration associated with aging.
Stefan Stamenkovic, Franca Schmid, Gokce Gurler ...
· Nature neuroscience
· Center for Developmental Biology and Regenerative Medicine, Seattle Children's Research Institute, Seattle, WA, USA.
· pubmed
The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or a consequence remains debatable. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in c...
The progressive loss of cerebral white matter during aging contributes to cognitive decline, but whether reduced blood flow is a cause or a consequence remains debatable. Using deep multi-photon imaging in mice, we examined microvascular networks perfusing myelinated tissues in cortical layer 6 and the corpus callosum. We identified sparse, wide-reaching venules, termed principal cortical venules, which exclusively drain deep tissues and resemble the vasculature at the human cortex and U-fiber interface. Aging led to selective constriction and rarefaction of capillaries in deep branches of principal cortical venules. This resulted in mild hypoperfusion that was associated with microgliosis, astrogliosis and demyelination in deep tissues, but not the upper cortex. Induction of comparable hypoperfusion in adult mice using carotid artery stenosis triggered a similar tissue pathology specific to layer 6 and the corpus callosum. Thus, impaired capillary-venous drainage is a contributor to hypoperfusion and a potential therapeutic target for preserving blood flow to white matter during aging.
Longevity Relevance Analysis
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Impaired capillary-venous drainage contributes to hypoperfusion and tissue pathology in aging white matter. The study addresses a potential root cause of cognitive decline associated with aging, focusing on the mechanisms of blood flow impairment in the brain, which is relevant to longevity research.
Kim, C., Ofria, L. D., Kshirsagar, A. ...
· bioengineering
· The University of Texas at Austin
· biorxiv
Aging is increasingly recognized as a systemic process, yet the mechanisms by which senescent cells signal from peripheral tissues accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to ...
Aging is increasingly recognized as a systemic process, yet the mechanisms by which senescent cells signal from peripheral tissues accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to investigate how peripheral aging signals reshape brain tissue architecture. We combined spatially resolved optical fiber-based interferometry nanoindentation with transcriptomic and immunofluorescence profiling, demonstrating that bone-derived senescence-associated secretory phenotype (SASP) factors induce a biphasic mechanical response, early global tissue softening, followed by the emergence of discrete hyper-stiff microdomains. This spatially heterogeneous biomechanical remodeling was accompanied by upregulation of extracellular matrix (ECM), inflammatory, and senescence pathways, and suppression of neurodevelopmental and synaptic gene networks. Our results reveal that chronic paracrine SASP exposure from senescent osteocytes drives localized ECM reorganization and mechanical vulnerability in human brain tissue, providing mechanistic insight into how peripheral cellular senescence may contribute to regional brain fragility during aging.
Longevity Relevance Analysis
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Chronic exposure to senescent osteocyte secretome induces biomechanical vulnerability and ECM remodeling in human brain organoids. This study addresses the mechanisms by which peripheral cellular senescence contributes to brain aging, aligning with the investigation of root causes of aging.
Robert G Leija, José Pablo Vázquez-Medina, George A Brooks
· American journal of physiology. Endocrinology and metabolism
· Exercise Physiology, Department of Integrative Biology, University of California, Berkeley, CA 94720-3140.
· pubmed
Resting and maximal exercise respiratory rates (V̇O
Resting and maximal exercise respiratory rates (V̇O
Longevity Relevance Analysis
(4)
The paper claims that the resilience of the mitochondrial reticulum plays a crucial role in the aging process. This research is relevant as it addresses mitochondrial function, which is a key factor in the aging process and could provide insights into potential interventions for longevity.
Watrous, J. D., Tiwari, S., Long, T. ...
· biochemistry
· Sapient Bioanalytics, LLC
· biorxiv
Mass spectrometry (MS)-based metabolomics is a key technology for the interrogation of exogenous and endogenous small molecule mediators that influence human health and disease. To date, however, low throughput of MS systems have largely precluded large-scale metabolomics studies...
Mass spectrometry (MS)-based metabolomics is a key technology for the interrogation of exogenous and endogenous small molecule mediators that influence human health and disease. To date, however, low throughput of MS systems have largely precluded large-scale metabolomics studies of human populations, limiting power to discover physiological roles of metabolites. Here, we introduce a fully automated rapid liquid chromatography-mass spectrometry (rLC-MS) system coupled to an AI-enabled computational pipeline that enables high-throughput, reproducible, non-targeted metabolite measurements across tens of thousands of samples. This system captures thousands of polar, amphipathic and nonpolar (lipid) metabolites in a human plasma sample in 53 seconds of analytical time, enabling analysis of greater than 1,000 samples per day per instrument. To demonstrate the discovery power of the rLC-MS platform, a subset of samples from Sapient\'s DynamiQ biorepository -- comprised of 62,039 total plasma samples collected longitudinally from 11,045 individuals -- were selected for deep analysis by rLC-MS to capture a rich, dynamic landscape of chemical variation that reflects both physiological processes and environmental influences. 26,042 plasma samples with matched real-world data (RWD) were chosen for the study, representing 6,935 individuals with diverse demographic backgrounds and disease profiles. Unbiased exploratory analysis revealed human metabotypes that correlate with heterogenous disease phenotypes, including key sub-populations of cardiometabolic and other human diseases. Moreover, a metabolic aging clock machine learning model trained on healthy individuals in this dataset accurately predicted accelerated aging in various chronic diseases, with dynamic reversal of metabolic aging following definitive therapy. These data demonstrate that the rLC-MS platform enables prediction of clinically relevant physiological states from plasma metabolomics at scale in human populations.
Longevity Relevance Analysis
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The paper claims that the rLC-MS platform can predict clinically relevant physiological states from plasma metabolomics at scale in human populations. This research is relevant as it explores metabolic aging and its correlation with chronic diseases, potentially addressing underlying mechanisms of aging rather than merely treating symptoms.
Ogg, M., Coon, W. G.
· neurology
· Johns Hopkins University Applied Physics Laboratory
· medrxiv
Biological age estimation, derived from physiological signatures such as brain activity, is emerging as a valuable biomarker for health and well-being. Discrepancies between biological and chronological age have been linked to multiple physical, mental, and cognitive health outco...
Biological age estimation, derived from physiological signatures such as brain activity, is emerging as a valuable biomarker for health and well-being. Discrepancies between biological and chronological age have been linked to multiple physical, mental, and cognitive health outcomes. However, current approaches primarily focus on MRI-based measurements, which are costly, challenging to obtain, and contraindicated for certain populations. This study explores polysomnographic (PSG) sleep signals, which capture activity from multiple physiological systems, as an accessible alternative for biological age prediction. Sleep serves as an ideal platform for age prediction due to its standardized data collection protocols, abundant public data resources, and the presence of well-documented age-related changes in sleep architecture. Additionally, the proliferation of consumer sleep monitoring tools offers potential for widespread application and longitudinal analysis. We trained transformer-based neural network models on over 10,000 nights of PSG data and performed rigorous internal and external validation. Our best models achieved age predictions with an absolute error of 5-10 years from just a single physiological time series input and were especially accurate with respect to certain stages of sleep (specifically, N2). Electroencephalography (EEG) signals were essential for capturing sleep architecture changes that correlate with age, while electrocardiogram (ECG) signals, although less accurate overall, tended to overestimate age in association with health conditions such as elevated blood pressure, higher body mass index, and sleep apnea. Despite strong performance, generalization beyond the training dataset remains a challenge (age prediction errors increase between internal validation and external data by at least 3 to 5 years). These findings show that noninvasive sleep-derived electrophysiological signals, particularly EEG, can rival MRI-based age prediction models in accuracy-while offering lower cost, greater accessibility, and broader applicability.
Longevity Relevance Analysis
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The paper claims that transformer models can accurately predict biological age from sleep physiology data. This research is relevant as it explores noninvasive methods for biological age estimation, which could contribute to understanding aging processes and improving health outcomes related to aging.
Eun-Ha Kim, Ho Bin Jang, Se-Mi Kim ...
· B-Lymphocytes
· Center for Virus Research Resource, Korea Virus Research Institute, Institute for Basic Science (IBS), Daejeon, Republic of Korea.
· pubmed
Aging significantly influences host immune responses to viral infections, including Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), which is associated with high mortality in elderly patients. Despite its high fatality rate and pandemic potential, effective therapies r...
Aging significantly influences host immune responses to viral infections, including Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), which is associated with high mortality in elderly patients. Despite its high fatality rate and pandemic potential, effective therapies remain unavailable, and the age-dependent mechanisms underlying SFTSV pathogenesis are not fully understood. To address this gap, we employed a ferret model (an immunocompetent animal model that mimics human SFTSV infections) and performed multi-tissue single-cell RNA sequencing and histopathological analyses. Our results reveal that, upon SFTSV infection, aged ferrets experience extensive decrease of critical immune cells (particularly B and T cells) due to infection-induced cell death and excessive hemophagocytosis in hematopoietic organs, whereas young-adult ferrets rapidly clear the virus with minimal lymphocyte changes. Notably, aged ferrets display marked immune dysregulation, characterized by non-specific activation of T-bet ⁺ age-associated memory B cells (T-bet+ ABCs) and the proliferation of defective plasmablasts (MKI67 ⁺ PB1), which serve as major viral reservoirs and drive systemic viral dissemination. Comparative analysis further demonstrated that the MKI67 ⁺ PB1 subset dominates SFTSV⁺ cells in both aged ferrets and human fatal cases, exhibiting the highest per-cell viral UMI counts. Moreover, monocytes and macrophages in aged ferrets exhibit heightened inflammatory gene expression, contributing to the hyper-inflammatory state observed during infection. Collectively, these insights underscore the critical role of dysregulated memory B cell responses and hyper-inflammation in age-dependent SFTSV pathogenesis, highlighting potential targets for interventions in elderly populations.
Longevity Relevance Analysis
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Aged ferrets exhibit immune dysregulation and B cell dysfunction that contribute to severe outcomes in SFTSV infection. The paper addresses age-related immune mechanisms that could inform interventions targeting the aging process and its effects on viral infections, making it relevant to longevity research.
Kirsten C Sadler, Mekayla A Storer, N Sumru Bayin
· The FEBS journal
· Program in Biology and Center for Genomics and Systems Biology, NYU Abu Dhabi, UAE.
· pubmed
A strong regenerative capacity is a hallmark of youth. From the tadpole's tail to the mammalian brain, young animals of many species can repair or regrow damaged tissues more effectively than older animals. Here, we take a broad perspective on ageing, inclusive of the transition ...
A strong regenerative capacity is a hallmark of youth. From the tadpole's tail to the mammalian brain, young animals of many species can repair or regrow damaged tissues more effectively than older animals. Here, we take a broad perspective on ageing, inclusive of the transition from the developmental processes of embryogenesis through maturation to adulthood, as well as the processes that occur as an animal reaches the end of its lifespan. In some cases, the loss of regenerative capacity occurs once development is complete, and in others it occurs in the latter part of the animal's life. Regardless, the loss of regenerative capacity is caused by a failure to activate genes required for successful regeneration. This, in part, can be attributed to restructuring of the epigenome.
Longevity Relevance Analysis
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The paper claims that the loss of regenerative capacity with age is due to epigenomic restructuring that prevents the activation of necessary genes for regeneration. This research addresses the underlying mechanisms of aging and regeneration, which are crucial for understanding longevity and potential lifespan extension.
Ryo Murayama, Kenichi Horisawa, Shizuka Miura ...
· Aging cell
· Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
· pubmed
Aging causes significant changes in gene expression and metabolic function of cells in various organs. Although it is known that liver regeneration is delayed by aging, the effects of aging on changes in gene expression and metabolic functions in liver regeneration need further i...
Aging causes significant changes in gene expression and metabolic function of cells in various organs. Although it is known that liver regeneration is delayed by aging, the effects of aging on changes in gene expression and metabolic functions in liver regeneration need further investigation. In this study, we comprehensively analyzed changes in gene expression and metabolic function by liver regeneration in young and old mice to examine the effects of aging on these changes. During the process of liver regeneration, the gene expression profiles of hepatocytes from young and old mice changed significantly in a stepwise manner while each remained close together. After the completion of liver regeneration, the genes with aging-specific expression patterns in old mouse hepatocytes changed to expression levels close to those in young mouse hepatocytes. In contrast to the results of these transcriptome analyses, the aging-specific changes in metabolic state detected in old mouse livers were found to be largely maintained after the completion of liver regeneration. These results demonstrated that the gene expression state in the liver of old mice is flexibly altered by liver regeneration, whereas their metabolic state is robust. This finding helps to elucidate the relationship between aging and liver regeneration and to determine the basis of the increased incidence of liver disease with aging.
Longevity Relevance Analysis
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The paper claims that liver regeneration alters gene expression in old mice, but their metabolic state remains unchanged. This research is relevant as it explores the relationship between aging and liver regeneration, contributing to understanding the biological mechanisms underlying age-related changes and potential interventions.
Yifan Xiang, Vineeta Tanwar, Parminder Singh ...
· Menarche
· The Buck Institute for Research on Aging, Novato, United States.
· pubmed
Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antag...
Aging can be understood as a consequence of the declining force of natural selection with age. Consistent with this, the antagonistic pleiotropy theory of aging proposes that aging arises from trade-offs that favor early growth and reproduction. However, evidence supporting antagonistic pleiotropy in humans remains limited.
Longevity Relevance Analysis
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Early menarche and childbirth are linked to accelerated aging-related outcomes and age-related diseases. This paper explores the relationship between reproductive factors and aging, contributing to the understanding of the biological mechanisms underlying aging and potential interventions.
Evgeniia Bakaleinikova
· Aging
· Western Governors University, Millcreek, UT, USA. [email protected].
· pubmed
Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms drivin...
Aging is increasingly understood as a multifactorial process involving mitochondrial dysfunction, epigenetic drift, and chronic inflammation. While many age-related pathologies have been linked to impaired mitophagy and transcriptional deregulation, the upstream mechanisms driving these phenomena remain elusive. Here, a unifying hypothesis is proposed: that the progressive reactivation of human endogenous retroviruses (HERVs), combined with latent viral infections acquired during life, imposes an escalating burden on the epigenetic regulatory system. This "virome pressure" demands continuous silencing via DNA methylation, histone deacetylation, and NAD⁺-dependent pathways. With age, these silencing mechanisms deteriorate, leading to HERV reactivation, disruption of key mitochondrial quality control genes, and activation of innate immune responses. This is likened to a molecular peat bog, a simmering threat buried beneath the surface, where silencing mechanisms struggle to contain viral elements until pressure builds and erupts as the organism ages. This model integrates virology, epigenetics, and mitochondrial biology to offer novel insights into the aging process and suggests new targets for therapeutic intervention research.
Longevity Relevance Analysis
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The paper proposes that reactivation of endogenous retroviruses and latent viral infections contributes to epigenetic drift and mitophagy failure in aging. This research addresses potential root causes of aging by linking viral reactivation to epigenetic and mitochondrial dysfunction, which are critical factors in the aging process.
Boyang Li, Shaowei Wang, Bilal Kerman ...
· Aging cell
· Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
· pubmed
Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism...
Cellular senescence is a major contributor to aging-related degenerative diseases, including Alzheimer's disease (AD), but much less is known about the key cell types and pathways driving senescence mechanisms in the brain. We hypothesized that dysregulated cholesterol metabolism is central to cellular senescence in AD. We analyzed single-cell RNA-seq data from the ROSMAP and SEA-AD cohorts to uncover cell type-specific senescence pathologies. In ROSMAP snRNA-seq data (982,384 nuclei from postmortem prefrontal cortex), microglia emerged as central contributors to AD-associated senescence phenotypes among non-neuronal cells. Homeostatic, inflammatory, phagocytic, lipid-processing, and neuronal-surveillance microglial states were associated with AD-related senescence in both ROSMAP (152,459 microglia nuclei from six brain regions) and SEA-AD (82,486 microglia nuclei) via integrative analysis. We assessed top senescence-associated bioprocesses and demonstrated that senescent microglia exhibit altered cholesterol-related processes and dysregulated cholesterol metabolism. We identified three gene co-expression modules representing cholesterol-related senescence signatures in postmortem brains. To validate these findings, we applied these signatures to snRNA-seq data from iPSC-derived microglia(iMGs) exposed to myelin, Aβ, apoptotic neurons, and synaptosomes. Treatment with AD-related substrates altered cholesterol-associated senescence signatures in iMGs. This study provides the first human evidence that dysregulated cholesterol metabolism in microglia drives cellular senescence in AD. Targeting cholesterol pathways in senescent microglia is an attractive strategy to attenuate AD progression.
Longevity Relevance Analysis
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Dysregulated cholesterol metabolism in microglia drives cellular senescence in Alzheimer's disease. The paper addresses a potential root cause of aging-related pathology by linking cholesterol dysregulation in microglia to cellular senescence, which is a significant aspect of aging and age-related diseases.
Anyu Zeng, Hailong Liu, Shuling He ...
· DNA Methylation
· Department of Bone and Soft Tissue Surgery, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, 510080, P. R. China.
· pubmed
Skeletal muscle stem cells (MuSCs) have strong regenerative abilities, but as we age, their ability to regenerate decreases, leading to a decline in muscle function. Although the methylation reprogramming of super-enhancers (SEs) plays a pivotal role in regulating gene expression...
Skeletal muscle stem cells (MuSCs) have strong regenerative abilities, but as we age, their ability to regenerate decreases, leading to a decline in muscle function. Although the methylation reprogramming of super-enhancers (SEs) plays a pivotal role in regulating gene expression associated with the aging process, our understanding of the molecular diversity of stem cells during aging remains limited. This study aimed to identify the methylation profile of SEs in MuSCs and explore potential therapeutic molecular targets associated with aging.
Longevity Relevance Analysis
(4)
The paper claims to identify the methylation profile of super-enhancers in skeletal muscle stem cells and explore therapeutic targets related to aging. This research is relevant as it addresses the molecular mechanisms underlying the decline in regenerative abilities of muscle stem cells with age, which is a fundamental aspect of the aging process.
Athanasios Siametis, George A Garinis
· BioEssays : news and reviews in molecular, cellular and developmental biology
· Institute of Molecular Biology and Biotechnology (IMBB), Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece.
· pubmed
Persistent genomic instability compromises cellular viability while also triggers non-cell-autonomous responses that drive dysfunction across tissues, contributing to aging. Recent evidence suggests that DNA damage activates secretory programs, including the release of inflammato...
Persistent genomic instability compromises cellular viability while also triggers non-cell-autonomous responses that drive dysfunction across tissues, contributing to aging. Recent evidence suggests that DNA damage activates secretory programs, including the release of inflammatory cytokines, damage-associated molecular patterns, and extracellular vesicles, that reshape immune homeostasis, stem cell function, and metabolic balance. Although these responses may initially support tissue integrity and organismal survival, their chronic activation has been associated with tissue degenerative changes and systemic decline. Here, we discuss how nuclear DNA damage responses trigger the activation of cytoplasmic sensing pathways, promote secretory phenotypes, and affect organismal physiology. Targeting DNA damage-driven mechanisms may help buffer harmful systemic responses while preserving regeneration and immune surveillance, offering new ways to delay aging-related decline.
Longevity Relevance Analysis
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Chronic activation of DNA damage responses leads to systemic decline and may be targeted to delay aging-related degeneration. The paper addresses the root causes of aging by exploring how DNA damage contributes to systemic dysfunction, which is central to longevity research.
Miras Moreno, S., Torres, A., Ruiz, J. ...
· epidemiology
· University of Almeria
· medrxiv
Cardiorespiratory fitness (CRF) is a strong predictor of mortality and non-communicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified CRF associated metabolomics (n=30,010) and proteomics (n=4,235) signatures in UK Bioba...
Cardiorespiratory fitness (CRF) is a strong predictor of mortality and non-communicable disease risk, but its underlying molecular mechanisms are poorly understood. In this study, we identified CRF associated metabolomics (n=30,010) and proteomics (n=4,235) signatures in UK Biobank participants. These signatures were validated in an independent sample of UK participants with data on metabolomics (n=198,871) and proteomics (n=29,961) to investigate prospective associations with all-cause mortality and non-communicable diseases. Our findings reveal that higher CRF is characterized by downregulation of pathways related to inflammation, triglyceride metabolism, glycolysis, and vascular dysfunction, and upregulation of pathways related to cholesterol transport, apolipoprotein particle size, and cytoskeletal remodeling. Leveraging these insights, we developed two novel metabolic CRF signatures, one metabolomic and one proteomic, that robustly reflect CRF levels (R2: 0.49-0.60). Over an average of 9 years of follow-up, we observed 27,659 cases of all-cause mortality. Across the discovery and validation cohorts, we found that the metabolomic CRF signature was strongly associated with a 34-39% lower risk of all-cause mortality and markedly reduced risk of type 2 diabetes (89-91%), cardiovascular disease (35-39%), and colorectal cancer (32-54%). Additionally, the proteomic CRF signature was associated with a 17% lower risk of all-cause mortality, and with a 22-39% lower risk of type 2 diabetes and cardiovascular disease. Together, these findings suggest that circulating metabolites and proteins can capture the physiological imprint of CRF and may serve as indirect biomarkers for predicting mortality and non-communicable disease risk.
Longevity Relevance Analysis
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The paper claims that specific metabolomic and proteomic signatures associated with cardiorespiratory fitness can predict all-cause mortality and non-communicable disease risk. This research is relevant as it explores the molecular mechanisms underlying cardiorespiratory fitness, which is a significant factor in longevity and age-related health outcomes.
Leite, J. A., Ergun, Z., Stylianakis, E. ...
· immunology
· University Medical Center Mainz
· biorxiv
Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the contex...
Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the context of age-related inflammation remains poorly understood. Here we demonstrate that age-related changes in the microbiota promote impaired Treg cell function, resulting in the differentiation of inflammatory T cells. In agreement, we find that aged germ-free (GF) mice exhibited a more balanced immune profile, where the Treg cells are functional and pro-inflammatory mediators are reduced, suggesting that microbial exposure is essential for the establishment of inflammaging. Furthermore, we show that the use of old microbiota in young animals was sufficient to induce pro-inflammatory T cell responses and impaired mucosal Treg cell proliferation, while young microbiota restored Treg cell function in old animals. Mechanistically, we show that exposure to aged microbiota was associated with sustained TNF signaling, elevated oxidative stress, DNA damage, and increased expression of senescence markers such as {gamma}H2AX and p16 in Treg cells. These findings uncover a microbiota-TNF- dependent mechanism by which age-associated microbial dysbiosis drives Treg cell dysfunction and promotes immune aging, highlighting the therapeutic potential of microbiota-targeted strategies to restore immune homeostasis in the elderly.
Longevity Relevance Analysis
(4)
Age-related changes in the microbiota impair Treg cell function through TNF signaling, contributing to immune aging. This paper is relevant as it addresses a potential root cause of aging by exploring the microbiota's role in immune dysfunction, which could lead to therapeutic strategies for restoring immune homeostasis in the elderly.
Maxim N Shokhirev, Adiv A Johnson
· GeroScience
· Tally Health, New York, NY, USA. [email protected].
· pubmed
Using 100 technical replicate samples from two adult buccal cohorts, we compared technical methylation variability and signal strength between the Infinium MethylationEPIC v2.0 array and the Twist Human Methylome Panel across 753,648 shared CpGs. Twist methylation sequencing show...
Using 100 technical replicate samples from two adult buccal cohorts, we compared technical methylation variability and signal strength between the Infinium MethylationEPIC v2.0 array and the Twist Human Methylome Panel across 753,648 shared CpGs. Twist methylation sequencing showed skewed methylation distributions and fewer highly correlated CpGs than MethylationEPIC arrays. Variance analysis revealed a skew toward higher signal strength in MethylationEPIC datasets, with a subset of CpGs showing high signal strength in both methylation sequencing and array datasets. Despite these biases, four principal component (PC) trained epigenetic clocks (pcHorvath1, pcHorvath2, pcHannum, and pcDNAm PhenoAge) were robust across both technologies, even with missing data. While pcHannum and pcDNAm PhenoAge were similarly reproducible with mean absolute replicate difference (MRD) values ranging from 1.014 years to 1.194 years, pcHorvath1 was more reproducible in arrays (MRD = 0.459 years) than methylation sequencing (MRD = 2.320 years) and pcHorvath2 was more reproducible in methylation sequencing (MRD = 0.760 years) than arrays (MRD = 1.011 years). Furthermore, original non-PC versions of these clocks were less reproducible in Twist datasets and, as an example of this, MRD for uncorrected clocks went as high as 15.498 years in arrays and as high as 20.180 years in methylation sequencing. Obvious differences in age prediction were also observed in original clocks compared to their PC-trained versions across both technologies (with a mean absolute difference ranging from 4.492 years to 46.724 years). This underscores the need for careful selection of epigenetic clocks and technology-specific adjustments when optimizing for accuracy and reproducibility.
Longevity Relevance Analysis
(4)
The paper demonstrates that different epigenetic clocks exhibit varying levels of reproducibility across methylation technologies, highlighting the importance of technology-specific adjustments for accurate age prediction. This research is relevant as it addresses the measurement of biological age, which is a key factor in understanding the aging process and potential interventions for lifespan extension.
Wan-Hsuan Lu, Sophie Guyonnet, Jérémy Raffin ...
· Aging cell
· IHU HealthAge, Toulouse, France.
· pubmed
Evidence connecting skin aging to functional decline and systemic aging biomarkers is lacking. This study investigated how skin-aging biomechanics were associated with changes in intrinsic capacity (IC), a marker of healthy aging. We also explored their links with biological agin...
Evidence connecting skin aging to functional decline and systemic aging biomarkers is lacking. This study investigated how skin-aging biomechanics were associated with changes in intrinsic capacity (IC), a marker of healthy aging. We also explored their links with biological aging clocks (epigenetic and inflammatory clocks) and potential moderating effects on the skin-IC relationship. Baseline skin elasticity and viscoelasticity were measured in 441 INSPIRE-T participants aged 20 to 93 (59.9% women) using Cutometer parameters. IC was evaluated over 3 years as a five-domain score covering cognition, locomotion, psychology, vitality, and sensory (a higher score indicated better). Biological aging was measured at baseline using six epigenetic clocks (Horvath pan-tissue, Horvath skin & blood, Hannum, PhenoAge, GrimAge, and DunedinPACE) and inflammatory clock (iAge). Poor skin elasticity and viscoelasticity in older adults were associated with lower baseline IC after controlling for demographic, medical, and lifestyle factors. Longitudinally, older men with a higher viscoelastic ratio (R6) experienced a faster decline in IC (a standardized coefficient [95% CI] ranged from -0.37 [-0.72, -0.03] at age 62 to -1.32 [-1.91, -0.73] at age 93). Accelerated iAge was associated with reduced skin elasticity (R2, R5, R7). Moreover, the association between parameters related to elastic recovery (R5, R7) and baseline IC became more pronounced as accelerated iAge increased. This is the first study demonstrating the association between skin-aging biomechanics and IC. Poor skin elasticity was associated with higher systemic inflammation. Therefore, skin biomechanical properties may reflect overall functional aging, with inflammation serving as a common underlying factor.
Longevity Relevance Analysis
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The paper claims that poor skin biomechanical properties are associated with lower intrinsic capacity and higher systemic inflammation in older adults. This research is relevant as it explores the connections between skin aging, functional decline, and biological aging markers, contributing to the understanding of aging mechanisms.
Andrea Castegnaro, Alexander Dior, Neil Burgess ...
· Psychology and aging
· Institute of Cognitive Neuroscience, University College London.
· pubmed
Navigational skills are essential for interacting with our environment, supported by multiple types of spatial representations. We investigated age-related differences in spatial memory using a virtual reality task that manipulated viewpoints between the encoding and retrieval of...
Navigational skills are essential for interacting with our environment, supported by multiple types of spatial representations. We investigated age-related differences in spatial memory using a virtual reality task that manipulated viewpoints between the encoding and retrieval of one or four-object locations. The task investigates compensatory mechanisms in aging, specifically how spatial updating via self-motion affects spatial memory. We tested 21 young adults (ages 19-36) and 23 older adults (ages 63-80). The task involved three movement conditions: same-viewpoint condition, where participants walked away and returned to the same viewpoint; shifted-viewpoint (walking) condition where participants walked to a different viewpoint, enabling continuous updates of their egocentric representations through self-motion; and shifted-viewpoint (teleport) condition where participants teleported to the other viewpoint, involving both a virtual translation and rotation of the participant's view. Retrieval was tested by asking participants to place each object at its previously seen location. Average displacement error was affected by age group, object configuration, and movement condition, with an interaction between age and movement condition. Differences in movement conditions were primarily driven by older participants, who were most accurate from the same viewpoint. In shifted-viewpoint conditions, teleportation-where self-motion cues were absent-led to significantly greater errors than walking in the older group. Our results highlight the role of spatial updating in supporting spatial memory and suggest that age-related decline in allocentric representations can be mitigated by continuous updating of egocentric representations by self-motion. We speculate that the use of spatial updating might be impaired early in the progression to Alzheimer's dementia due to entorhinal cortical pathology. (PsycInfo Database Record (c) 2025 APA, all rights reserved).
Longevity Relevance Analysis
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The paper claims that spatial updating via self-motion can mitigate age-related decline in allocentric spatial memory. This research is relevant as it explores cognitive mechanisms that could potentially address aspects of aging and their implications for conditions like Alzheimer's disease.
Raymond Laboy, Marjana Ndoci, Shamsh Tabrez Syed ...
· Hexokinase
· Department of Molecular Genetics of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany.
· pubmed
The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in
The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in
Longevity Relevance Analysis
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Hexokinase regulates Mondo-mediated longevity through the pentose phosphate pathway and organellar dynamics. The paper addresses mechanisms that may influence longevity pathways, which is directly related to understanding and potentially mitigating the aging process.
Yuko Maejima, Shoko Yokota, Megumi Yamachi ...
· Aging cell
· Department of Bioregulation and Pharmacological Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan.
· pubmed
While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation...
While it is well-documented that plasma oxytocin (OXT) levels decline with age, the underlying mechanisms remain elusive. This study aimed to elucidate the physiological mechanisms contributing to this age-related decrease in plasma OXT and the possible use of OXT supplementation on improving age-related decline of neural function. Comparing young (9 weeks) and aged (> 45 weeks) mice, aged mice showed reduced plasma OXT levels, an increase in the inflammation marker hs-CRP, and decreased OXT-positive neurons in the hypothalamus. Aged mice showed signs of epigenetic changes in the hypothalamus as indicated by decreased ten-eleven translocation (TET) family mRNA expression, decreased 5-hydroxymethylcytosine (5hmC) positive neurons, and downregulated mitochondrial respiratory complex IV (COX IV) expression. Nasal application of OXT (10 μg/day) for 10 days to aged mice resulted in normalized plasma OXT and inflammation levels and a recovery of OXT-positive neurons, TET2 mRNA levels, 5hmC positive neurons, and COX IV expression. Directly confirming a role for OXTR signaling, TET2, COX IV, and 5hmC in the hypothalamus and hippocampus were also found to be decreased in oxytocin receptor (OXTR) null mice, compared with age-matched WT mice. Furthermore, we show that methylation as a result of aging decreases OXT production in hypothalamic neurons, thereby reducing circulating plasma OXT levels, which can be reversed by nasal OXT treatment. The data presented here suggest that aging, DNA methylation, mitochondrial dysfunction, inflammation, and senescence are interconnected in a vicious cycle, which can be successfully interrupted by OXT treatment.
Longevity Relevance Analysis
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Oxytocin supplementation can reverse age-related declines in neural function by enhancing demethylation through TET enzyme expression. The study addresses the mechanisms of aging and suggests a potential intervention to mitigate age-related decline, making it relevant to longevity research.
The MULTI Study, , O'Toole, C. K., Song, Z. ...
· health informatics
· Columbia University
· medrxiv
Optimal sleep plays a vital role in promoting healthy aging and enhancing longevity. This study proposes a Sleep Chart to assess the relationship between sleep duration and 23 biological aging clocks across 17 organ systems or tissues and 3 omics data types (imaging, proteomics, ...
Optimal sleep plays a vital role in promoting healthy aging and enhancing longevity. This study proposes a Sleep Chart to assess the relationship between sleep duration and 23 biological aging clocks across 17 organ systems or tissues and 3 omics data types (imaging, proteomics, and metabolomics). First, a systemic, U-shaped pattern shows that both short (<6 hours) and long (>8 hours) sleep duration are linked to elevated biological age gaps (BAGs) across 9 brain and body systems and 3 omics types, with optimal sleep time varying by organ and sex ([6.4-7.8] hours). Furthermore, short and long sleep duration, compared to a normal sleep duration ([6-8] hours), are consistently linked to increased risk of systemic diseases beyond the brain and all-cause mortality, with evidence from genetic correlations and time to incident disease predictions, such as migraine, depression, and diabetes. Finally, short and long sleep duration are associated with late-life depression via distinct pathways: long sleep may contribute indirectly through biological aging processes, while short sleep shows a more direct link. Although our Mendelian randomization does not show strong causal effects from disease to sleep disturbances, it does not fully rule out the possibility that sleep disturbances may, in part, reflect underlying disease burden. Our findings suggest that the U-shaped relationship is likely driven by modifiable sleep disturbances rather than genetic predisposition, highlighting the potential of sleep optimization to support healthy aging, lower disease risk, and extend longevity. An interactive web portal is available to explore the Sleep Chart at: https://labs-laboratory.com/sleepchart.
Longevity Relevance Analysis
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The study identifies a U-shaped relationship between sleep duration and biological aging clocks across various organ systems, suggesting that optimizing sleep can support healthy aging and lower disease risk. The paper is relevant as it explores modifiable factors that may influence biological aging and longevity, rather than merely addressing symptoms of age-related diseases.
Ying Huang, Zhenxing Zhou, Mengjia Huan ...
· Aging cell
· The Affiliated Eye Hospital, Nanjing Medical University, Nanjing, P. R. China.
· pubmed
Antioxidant decline is crucial to driving age-related macular degeneration (AMD). Ferroptosis, a regulated cell death mediated by iron-dependent hydroxyl radical-catalyzed phospholipid peroxidation through the Fenton reaction, is implicated in various chronic degenerative disease...
Antioxidant decline is crucial to driving age-related macular degeneration (AMD). Ferroptosis, a regulated cell death mediated by iron-dependent hydroxyl radical-catalyzed phospholipid peroxidation through the Fenton reaction, is implicated in various chronic degenerative diseases. Here, we show that superoxide activates ferroptosis in retinal pigment epithelium (RPE) cells via the Haber-Weiss reaction, thereby contributing to dry AMD. We silenced manganese superoxide dismutase (MnSOD/SOD2) in RPE cells and exposed the cells to blue light to induce ferroptosis by increasing superoxide anions. Additionally, MnSOD deficiency triggered the Hsp70-linked ubiquitin-dependent degradation of GPX4, further aggravating ferroptosis. We validated blue light-induced ferroptosis in the RPE layer as a driver of the dry AMD phenotype in Sod2
Longevity Relevance Analysis
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Superoxide activates ferroptosis in retinal pigment epithelium cells, contributing to age-related macular degeneration. The study addresses a mechanism related to oxidative stress and cell death in the context of aging, which is relevant to understanding and potentially mitigating age-related diseases.
A G Newman, J Sharif, P Bessa ...
· Heterochromatin
· Institute of Cell and Neurobiology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. [email protected].
· pubmed
In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs result...
In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs result in a chronic inflammatory environment characterized by neurodegeneration and cognitive decline in mice. We identify distinct roles for HP1 proteins to ERV silencing where HP1γ is necessary and sufficient for H4K20me3 deposition and HP1β deficiency causes aberrant DNA methylation. Combined loss of HP1β and HP1γ results in loss of DNA methylation at ERVK elements. Progressive ERV de-repression in HP1β/γ DKO mice is followed by stimulation of the integrated stress response, an increase of Complement 3+ reactive astrocytes and phagocytic microglia. This chronic inflammatory state coincides with age-dependent reductions in dendrite complexity and cognition. Our results demonstrate the importance of preventing loss of epigenetic maintenance that is necessary for protection of postmitotic neuronal genomes.
Longevity Relevance Analysis
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The paper claims that loss of heterochromatin maintenance and de-repression of endogenous retroviruses lead to chronic inflammation and cognitive decline in aging neurons. This research addresses the underlying mechanisms of aging-related cognitive decline, focusing on epigenetic maintenance as a potential target for interventions in age-related diseases.
Saptashwa Datta, Jen-Chieh Yu, Yi-Hsiang Lin ...
· Machine Learning
· Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan.
· pubmed
Aging is a natural phenomenon characterized by the loss of normal morphology and physiological functioning of the body, causing wrinkles on the skin, loss of hair, and compromised immune systems. Peptide therapies have emerged as a promising approach in aging studies because of t...
Aging is a natural phenomenon characterized by the loss of normal morphology and physiological functioning of the body, causing wrinkles on the skin, loss of hair, and compromised immune systems. Peptide therapies have emerged as a promising approach in aging studies because of their excellent tolerability, low immunogenicity, and high specificity. Computational methods can significantly expedite wet lab-based anti-aging peptide discovery by predicting potential candidates with high specificity and efficacy. We propose AAGP, an anti-aging peptide predictor based on diverse physicochemical and compositional features. Two datasets were constructed, both shared anti-aging peptides as positives, with the first using antimicrobial peptides as negatives and the second using random peptides as negatives. Peptides were encoded using 4,305 features, followed by adaptive feature selection with a heuristic algorithm on both datasets. Nine machine learning models were used for cross-validation and independent tests. AAGP achieves reasonably accurate prediction performance, with MCCs of 0.692 and 0.580 and AUCs of 0.963 and 0.808 on the two independent test datasets, respectively. Our feature importance analysis shows that physicochemical features are more crucial for the first dataset, whereas compositional features hold greater importance for the second. The source code of AAGP is available at https://github.com/saptawtf/AAGP .
Longevity Relevance Analysis
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The paper claims to present AAGP, a machine learning-based predictor for identifying anti-aging peptides. The research is relevant as it focuses on computational methods to discover peptides that may directly influence aging processes, rather than merely addressing age-related symptoms.
Jing-Yu Chang, Kuei-Ru Chou, Yu-Ling Chang ...
· Journal of physical activity & health
· Department of Psychology, College of Medical and Health Science, Asia University, Taichung, Taiwan.
· pubmed
Cognitive frailty, defined by the coexistence of physical frailty and mild cognitive impairment, can be reversed through targeted interventions. This meta-analysis evaluated the efficacy of physical activity interventions on cognitive function and well-being in older adults with ...
Cognitive frailty, defined by the coexistence of physical frailty and mild cognitive impairment, can be reversed through targeted interventions. This meta-analysis evaluated the efficacy of physical activity interventions on cognitive function and well-being in older adults with frailty.
Longevity Relevance Analysis
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Physical activity interventions can improve cognitive function and well-being in older adults with cognitive frailty. This paper addresses cognitive frailty, which is a significant aspect of aging and seeks to improve the quality of life in older adults, thus contributing to longevity research.
Bo Ma, Yuanxin Miao, Yan Xu ...
· NPJ science of food
· School of Food and Biology, Jingchu University of Technology, Jingmen, PR China.
· pubmed
This study evaluated the in vitro and in vivo antioxidant activities of puerarin (PUE) and β-lactoglobulin (β-lg). The results of the in vitro antioxidant assay revealed that the DPPH and ABTS radical scavenging rates of the PUE/β-lg complex were generally superior to those of fr...
This study evaluated the in vitro and in vivo antioxidant activities of puerarin (PUE) and β-lactoglobulin (β-lg). The results of the in vitro antioxidant assay revealed that the DPPH and ABTS radical scavenging rates of the PUE/β-lg complex were generally superior to those of free PUE within the tested experimental concentration range. The in vivo antioxidant activity assay, using Caenorhabditis elegans (C. elegans) as a model organism, showed that the PUE/β-lg complex significantly increased the superoxide dismutase (SOD) activity and reduced glutathione (GSH) content in C. elegans, and also increased the mean lifespan of C. elegans under oxidative and thermal stress conditions. Transcriptomic analysis showed that the PUE/β-lg complex regulated the mRNA expression levels of genes associated with the activation of various signaling pathways, such as the longevity regulation pathway, insulin signaling pathway, and GSH metabolism. Overall, this study demonstrated the potential of the PUE/β-lg complex as an antioxidant, which can lead to its development into food products or pharmaceuticals.
Longevity Relevance Analysis
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The study claims that the puerarin-β-lactoglobulin complex enhances antioxidant activity and increases lifespan in C. elegans. This research is relevant as it explores mechanisms that may contribute to longevity and lifespan extension through antioxidant pathways.
Saha, S., Chakraborty, P., Roy, D. ...
· neuroscience
· Indian Institute of Technology Jodhpur
· biorxiv
Aging brain undergoes a structural decline over lifespan accompanied by changes in neurotransmitter levels, leading to altered functional markers. Past studies have reported human resting state brain display a remarkable preservation of coordination among neural assemblies stemmi...
Aging brain undergoes a structural decline over lifespan accompanied by changes in neurotransmitter levels, leading to altered functional markers. Past studies have reported human resting state brain display a remarkable preservation of coordination among neural assemblies stemming from an underlying neurocomputational principles along aging trajectories, however, the true nature of which remains unknown. Here, we identify the computational mechanisms with which neurotransmitters, such as altered GABA and glutamate concentrations, can preserve functional integration across lifespan aging, despite structural decline. We employ multiscale, biophysically grounded modeling, constrained by the empirically derived anatomical connectome of the human brain, where the neurotransmitter concentrations can be free parameters that are algorithmically adjusted to maintain regional homeostasis and optimal working point. The two estimated neurotransmitters can maintain critical firing rates in the brain region and mimic age-associated functional connectivity patterns, consistent with empirical observations. We identified invariant GABA and reduced glutamate as the principle computational mechanism that can explain the topological variation of functional connectivity along lifespan, validated using graph-theoretic metrics. The results are subsequently replicated on three distinct datasets. Thus, the study offers an operational framework that integrates brain network dynamics at macroscopic and molecular scales, to gain insight into age-associated neural disorders.
Longevity Relevance Analysis
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The paper claims that invariant GABA and reduced glutamate concentrations can preserve functional integration in the aging brain despite structural decline. This research is relevant as it explores the underlying mechanisms of neural dynamics in aging, potentially addressing root causes of age-related cognitive decline.
Jihwan Myung, Hélène Vitet, Sheena Yin Xin Tiong
· Aging
· Graduate Institute of Mind, Brain and Consciousness (GIMBC), Taipei Medical University, Taipei, Taiwan. [email protected].
· pubmed
Circadian freerunning periods change across the lifespan, yet most computational models do not reproduce these shifts without assuming additional mechanisms. Although the maturation and later deterioration of the suprachiasmatic nucleus (SCN) shape behavioral and humoral rhythms,...
Circadian freerunning periods change across the lifespan, yet most computational models do not reproduce these shifts without assuming additional mechanisms. Although the maturation and later deterioration of the suprachiasmatic nucleus (SCN) shape behavioral and humoral rhythms, the underlying driver of period change is more general. We show that it arises from an inherent property of a positively skewed frequency distribution, which naturally follows from a symmetric Gaussian distribution of intrinsic periods. Using a Kuramoto framework with a time-dependent coupling strength and age-related widening of period variability, we map the geometry of synchronization and macroscopic period and trace a developmental trajectory across this surface. Strong coupling in early adulthood pulls the synchronized period below the mean, matching data from C57BL/6 mice, whereas declining coupling and greater heterogeneity in late life lengthen the period and reduce amplitude. The same mechanism explains the negative correlation between amplitude and macroscopic period when period variability is high. This "circadian geometry" reveals that age-dependent variations in the macroscopic period are sufficiently explained by coupling and the width of the period distribution, and provides a parsimonious framework applicable to the SCN and other oscillator populations for understanding long-term changes in circadian dynamics during development and aging.
Longevity Relevance Analysis
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The paper claims that age-dependent variations in circadian period can be explained by coupling strength and period distribution width. This research addresses fundamental mechanisms of circadian rhythms that change with aging, which is relevant to understanding the biological processes underlying aging and potential interventions.
Junrui Wang, Haoyuan Tian, Yuanyuan Gao ...
· Research (Washington, D.C.)
· Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Media, Nanjing University of Chinese Medicine, Nanjing 210023, China.
· pubmed
Activation of hepatic stellate cells (HSCs) represents a central pathological event in liver fibrogenesis, and targeted clearance of activated HSCs is considered to be a promising therapeutic strategy. However, our understanding of the underlying molecular mechanisms is limited. ...
Activation of hepatic stellate cells (HSCs) represents a central pathological event in liver fibrogenesis, and targeted clearance of activated HSCs is considered to be a promising therapeutic strategy. However, our understanding of the underlying molecular mechanisms is limited. Here, we report that Oroxylin A (OA) inhibited the activation of HSCs by inhibiting the dual roles of Sirtuin 7 (SIRT7). Single-cell transcriptome sequencing analysis and bioinformatics analysis were employed to identify critical pathways, followed by validation through molecular assays including Western blotting, immunofluorescence, and co-immunoprecipitation. In human samples, animal models, and primary cultures, the translational relevance of molecular discoveries was heightened. OA binds to the Gln299 and Asp305 residues of SIRT7, triggering a dual regulatory program in hepatic fibrosis. OA suppresses SIRT7, triggering succinylation-dependent proteasomal degradation of protein arginine methyltransferase 5 (PRMT5). This cascade attenuated symmetric dimethylation of cyclic GMP-AMP synthase (cGAS), thereby activating the cGAS-stimulator of interferon genes (STING) signaling and promoting HSC senescence. Concurrently, OA-elicited SIRT7 inhibition promotes externalized calreticulin (ecto-CRT) expression, thereby enhancing natural killer (NK) cell recognition and targeted elimination of activated HSCs. However, enzymatically dead mutant SIRT7 (H187Y) also suppressed ecto-CRT expression promoted by OA, showing that it is independent of its desuccinylase activity. Our findings reveal a dual regulatory mechanism whereby SIRT7 inhibition by OA coordinates PRMT5 degradation-mediated cellular senescence and ecto-CRT-dependent NK cell immune clearance of HSCs. This work establishes SIRT7 as a pivotal therapeutic target and provides mechanistic insights for developing antifibrotic strategies.
Longevity Relevance Analysis
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Oroxylin A inhibits SIRT7, leading to HSC senescence and enhanced NK cell clearance in liver fibrosis. The paper is relevant as it explores a potential therapeutic target (SIRT7) that could influence cellular aging processes and fibrosis, which are associated with age-related decline in liver function.
Weijia Zhang, Haoyu Ren, Wangwang Chen ...
· Cell death discovery
· The Fourth Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
· pubmed
Nicotinamide adenine dinucleotide (NAD⁺) is a critical coenzyme involved in cellular metabolism, energy balance, and various physiological processes. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in NAD⁺ synthesis, regulating the NAD⁺ regeneration p...
Nicotinamide adenine dinucleotide (NAD⁺) is a critical coenzyme involved in cellular metabolism, energy balance, and various physiological processes. Nicotinamide phosphoribosyltransferase (NAMPT) is a key rate-limiting enzyme in NAD⁺ synthesis, regulating the NAD⁺ regeneration pathway. This review summarizes the multiple roles of NAMPT in both physiological and pathological states, particularly in cellular stress, aging, metabolic disorders, and cancer. We first describe the central role of NAMPT in NAD⁺ synthesis and explore how NAD⁺ levels are regulated through NAMPT to control cellular functions and metabolic adaptation. Second, we analyze the pathological roles of NAMPT in aging and related diseases, highlighting how NAD⁺ depletion leads to mitochondrial dysfunction, DNA damage, and immune system dysregulation. Notably, NAMPT exacerbates cancer immune evasion mechanisms by influencing immune cell functions and the metabolic environment of tumors. We also discuss the potential of NAMPT as a therapeutic target, particularly through NAD⁺ precursor supplementation or the use of NAMPT activators and inhibitors to modulate NAD⁺ metabolism in aging, metabolic diseases, and cancer. Future research should focus on exploring the functional differences of NAMPT in various tissues and its therapeutic potential in disease treatment.
Longevity Relevance Analysis
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Nicotinamide phosphoribosyltransferase (NAMPT) plays a crucial role in regulating NAD⁺ levels, which are essential for cellular functions and metabolic adaptation in aging and related diseases. The paper is relevant as it addresses the role of NAMPT in NAD⁺ synthesis and its implications for aging and metabolic disorders, focusing on potential therapeutic targets that could influence the aging process.
Faith Morley, Lauren Mount, Anjile An ...
· Allostasis
· Department of Population Health Sciences, Weill Cornell Medicine, New York, New York, United States of America.
· pubmed
The rising prevalence of individuals reporting extreme stress has major public health implications as it increases vulnerability to accelerated premature biological aging, thus increasing risk of chronic disease. To examine the impact of stress on premature biological aging, we a...
The rising prevalence of individuals reporting extreme stress has major public health implications as it increases vulnerability to accelerated premature biological aging, thus increasing risk of chronic disease. To examine the impact of stress on premature biological aging, we assessed the association between exposure to increased stress, quantified by the Perceived Stress Scale, and odds of high allostatic load (AL). To illuminate previously unexplored socio-contextual factors, we controlled for self-reported individual and neighborhood social determinants of health that included discrimination, loneliness, food insecurity, neighborhood disorder, and neighborhood social cohesion. We utilized a cross-sectional design to examine the association between perceived stress and AL among 7,415 participants ages 18-65 in the All of Us Research Program, who enrolled from 2017-2022. We used logistic regression to evaluate the association between stress and high AL, controlling for sociodemographic factors and self-reported social determinants of health. Participants who were younger, receiving Medicaid, or Hispanic had increased prevalence of high stress. High stress was associated with elevated odds of high AL in age and sex-adjusted models (OR=2.18, 95%CI = 1.78, 2.66, high stress vs. low), an association which remained significant after adjusting for social determinants of health (OR=1.29, 95%CI = 1.01, 1.65). Using restricted cubic splines, high stress was significantly associated with increased odds of high AL, even after controlling for upstream individual and neighborhood-level determinants of health. While individuals living below the medium poverty-to-income ratio demonstrated little appreciable association between high stress and increased odds of high allostatic load, those living above the median poverty-to-income ratio reporting increased stress appeared to have increased odds of high allostatic load. Through addressing the upstream factors causing undue burdens of stress, which particularly affect marginalized communities and younger generations, we can begin to address premature biological aging and the comorbid conditions it accompanies.
Longevity Relevance Analysis
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High perceived stress is associated with increased odds of high allostatic load, particularly among marginalized communities. The paper addresses upstream factors contributing to stress and their impact on biological aging, which is relevant to understanding and potentially mitigating the root causes of aging.
Marena Gray, Oliver Boughton, Crispin Wiles ...
· Hip Fractures
· MSk Laboratory, Sir Michael Uren Hub, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, W12 0BZ, UK. [email protected].
· pubmed
Microdefects, including microcracks and resorption trenches, may be important contributors to bone fragility. 3D microdefect morphology was imaged using synchrotron micro-CT to develop a classification system for investigating the relationship with bone mechanics and hip-fracture...
Microdefects, including microcracks and resorption trenches, may be important contributors to bone fragility. 3D microdefect morphology was imaged using synchrotron micro-CT to develop a classification system for investigating the relationship with bone mechanics and hip-fractures. Femoral heads from ageing hip-fracture patients (n = 5, 74-82 years) were compared to ageing non-fracture controls (n = 5, 72-84 years). Two trabecular cores were prepared from the chiasma; one was imaged using synchrotron micro-CT to measure microdefects and one was mechanically tested to measure tensile strength. Morphological and mechanical data were compared and correlated using Mann Whitney U test and Pearson's rank correlation. All the procedures performed were in accordance with the ethical standards of the Imperial College Tissue Bank (R13004) and the 1984 Declaration of Helsinki. Microdefects varied and were classified into four categories based on shape and measurable parameters. Hip-fracture donors exhibited significantly higher density of all microdefects (p < 0.05). Microdefect volume was strongly negatively correlated with ultimate tensile strength (p < 0.05) and stiffness (p < 0.05). Microdefects might contribute to loss of bone strength and fragility fracture via runaway resorption. Microcracks could promote focussed osteoclastic resorption and the formation of resorption pits which create stress risers leading to the re-formation of microcracks under continued load. CT-based classification methods should be used to explore the complex interaction between microdefects, metabolism, and bone fracture mechanics.
Longevity Relevance Analysis
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Microdefects in bone contribute to loss of strength and fragility fractures in aging patients. The study addresses the underlying mechanisms of bone fragility, which is a significant aspect of age-related health decline.
Francesco Neri, Shuyuan Zheng, Mark A Watson ...
· Aging
· Buck Institute for Research on Aging, Novato, CA 94945 , USA.
· pubmed
Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies ident...
Cellular senescence has been strongly linked to aging and age-related diseases. It is well established that the phenotype of senescent cells is highly heterogeneous and influenced by their cell type and senescence-inducing stimulus. Recent single-cell RNA-sequencing studies identified heterogeneity within senescent cell populations. However, proof of functional differences between such subpopulations is lacking. To identify functionally distinct senescent cell subpopulations, we employed high-content image analysis to measure senescence marker expression in primary human endothelial cells and fibroblasts. We found that G2-arrested senescent cells feature higher senescence marker expression than G1-arrested senescent cells. To investigate functional differences, we compared IL-6 secretion and response to ABT263 senolytic treatment in G1 and G2 senescent cells. We determined that G2-arrested senescent cells secrete more IL-6 and are more sensitive to ABT263 than G1-arrested cells. We hypothesize that cell cycle dependent DNA content is a key contributor to the heterogeneity within senescent cell populations. This study demonstrates the existence of functionally distinct senescent subpopulations even in culture. This data provides the first evidence of selective cell response to senolytic treatment among senescent cell subpopulations. Overall, this study emphasizes the importance of considering the senescent cell heterogeneity in the development of future senolytic therapies.
Longevity Relevance Analysis
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G2-arrested senescent cells exhibit higher senescence marker expression and are more sensitive to senolytic treatment compared to G1-arrested cells. This study is relevant as it explores the heterogeneity of senescent cells, which is crucial for understanding and potentially targeting the root causes of aging and age-related diseases through senolytic therapies.
Domenico Azarnia Tehran, Paola Pizzo
· Aging
· Department of Biomedical Sciences, University of Padua, Padua, Italy. [email protected].
· pubmed
To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for c...
To sustain the essential biological functions required for life, eukaryotic cells rely on complex interactions between different intracellular compartments. Membrane contact sites (MCS), regions where organelles come into close proximity, have recently emerged as major hubs for cellular communication, mediating a broad range of physiological processes, including calcium signalling, lipid synthesis and bioenergetics. MCS are particularly abundant and indispensable in polarized and long-lived cells, such as neurons, where they support both structural and functional integrity. In this review, we explore the functional diversity, molecular composition, and dynamic regulation of key mammalian MCS: endoplasmic reticulum (ER)-plasma membrane, ER-mitochondria and contact sites involving lipid droplets. We highlight their central role in neuronal health and discuss how MCS dysfunction has increasingly been recognized as a hallmark of brain aging and various neurodegenerative diseases, most notably Alzheimer's disease, where altered MCS dynamics contribute to pathogenesis. Finally, we emphasize the therapeutic potential of targeting MCS and outline key unanswered questions to guide future research.
Longevity Relevance Analysis
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The paper claims that dysfunction of membrane contact sites (MCS) contributes to brain aging and neurodegeneration. The focus on MCS as a potential root cause of neurodegenerative diseases aligns with longevity research by exploring mechanisms that could influence aging processes.
Valentin Flietner, Bernd Heidergott, Frank den Hollander ...
· Aging
· PwC, Bernhard-Wicki-Strasse 8, 80636, Munich, Germany.
· pubmed
In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modelling of network evolutio...
In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modelling of network evolution with Poisson processes is universal and can be derived from fundamental principles. Second, with the help of two simplifying approximations, which we refer to as mean-field assumption and homogeneity assumption, we provide an analytical derivation of Gompertz law under generic and biologically relevant conditions. Third, we identify for which network parameters Gompertz law is accurate, express the parameters in Gompertz law as a function of the network parameters, and illustrate our computations with simulations and analytic approximations. Our paper is the first to offer a full mathematical explanation of Gompertz law and its limitations based on network theory.
Longevity Relevance Analysis
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The paper presents a mathematical model that explains Gompertz law in the context of aging and mortality through network theory. This work is relevant as it addresses fundamental aspects of aging and mortality, potentially contributing to a deeper understanding of the biological processes underlying aging.
Stephen B Kritchevsky, Steven R Cummings
· JAMA
· Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, and the Sticht Center for Healthy Aging and Alzheimer's Prevention, Wake Forest University of School of Medicine, Winston-Salem, North Carolina.
· pubmed
The incidence of stroke, heart failure, dementia, many cancers, coronary artery disease, and physical disability rise exponentially with age. Geroscience is a relatively new discipline that aims to define and modify aging-related biologic pathways, slow age-related disability, pr...
The incidence of stroke, heart failure, dementia, many cancers, coronary artery disease, and physical disability rise exponentially with age. Geroscience is a relatively new discipline that aims to define and modify aging-related biologic pathways, slow age-related disability, prevent age-related diseases, and increase disability-free survival.
Longevity Relevance Analysis
(5)
The paper discusses the potential to define and modify aging-related biologic pathways to prevent age-related diseases. This research is relevant as it addresses the root causes of aging and aims to extend healthspan and lifespan.
Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at...
Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at 3 time points corresponding to the peak of fibrosis, regeneration, and resolution. We find that lung injury shifts the transcriptomic profiles of three pulmonary capillary endothelial cells (PCEC) subpopulations. The associated signatures are linked to pro-angiogenic signaling with strong Lrg1 expression and do not progress similarly throughout the resolution process between young and old animals. Moreover, part of this set of resolution-associated markers is also detected in PCEC from samples of patients with idiopathic pulmonary fibrosis. Finally, we find that aging also alters the transcriptome of PCEC, which displays typical pro-fibrotic and pro-inflammatory features. We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation, thus contributing to the persistent fibrotic process typical of human pathology.
Longevity Relevance Analysis
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Aging alters the transcriptome of pulmonary capillary endothelial cells, impacting their role in lung injury resolution and fibrosis. The study addresses age-related changes in cellular mechanisms that contribute to fibrotic diseases, which is relevant to understanding the biological processes of aging and potential interventions.
Naru Sato, Susumu Goyama, Toshio Kitamura
· International journal of hematology
· Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. [email protected].
· pubmed
Clonal hematopoiesis (CH) is defined as the age-associated expansion of hematopoietic stem and progenitor cells harboring somatic mutations, most frequently in epigenetic regulators such as DNMT3A, TET2, and ASXL1. Although CH was initially recognized as a precursor to hematologi...
Clonal hematopoiesis (CH) is defined as the age-associated expansion of hematopoietic stem and progenitor cells harboring somatic mutations, most frequently in epigenetic regulators such as DNMT3A, TET2, and ASXL1. Although CH was initially recognized as a precursor to hematological malignancies, accumulating evidence has led to its broad recognition as a relevant factor in various age-related nonmalignant diseases, particularly those with inflammatory components, such as cardiovascular disease, autoimmune disorders, and solid tumors. Notably, the increased overall mortality associated with CH is primarily driven by cardiovascular complications rather than hematological malignancies. Among CH-associated genes, ASXL1 mutations are distinguished by their strong associations with adverse clinical outcomes and pro-inflammatory signatures. However, compared to TET2 and DNMT3A, the molecular and pathological implications of ASXL1-mutated CH remain underexplored. Recent studies have expanded the disease spectrum of ASXL1 mutations beyond hematological malignancies, implicating them in clonal expansion and systemic inflammation. This review aims to summarize the current epidemiological and experimental insights into ASXL1-mutated CH, focusing on its potential contributions to inflammation-associated diseases. By integrating clinical observations and emerging mechanistic data, we highlight the urgent need for deeper investigation into ASXL1-driven CH and its systemic consequences beyond hematological transformation.
Longevity Relevance Analysis
(4)
ASXL1 mutations in clonal hematopoiesis are linked to increased mortality and systemic inflammation in age-related diseases. The paper is relevant as it explores the underlying mechanisms of clonal hematopoiesis, which may contribute to the aging process and age-related diseases, rather than merely addressing symptoms.
van den Belt, M., van de Put, M., Yüksel, E. ...
· nutrition
· Vrije Universiteit Amsterdam, The Netherlands
· medrxiv
A randomized, placebo-controlled citizen science-based dietary intervention was conducted among 147 healthy adults to evaluate the effects of 8-week high dietary fiber (HDF) and high fermented food (HFF) diets on gut microbiota, immune function, gut transit time, well-being, and ...
A randomized, placebo-controlled citizen science-based dietary intervention was conducted among 147 healthy adults to evaluate the effects of 8-week high dietary fiber (HDF) and high fermented food (HFF) diets on gut microbiota, immune function, gut transit time, well-being, and sleep quality. The HDF group significantly increased fiber intake ({Delta}10.3 g/1000 kcal/day) following high dietary fiber recipes with addition of dried chicory root, while the HFF group increased fermented food consumption (+6.3 portions/day), including a fermentation-derived liquid supplement. At the 21-week follow-up, modest improvements in fiber and fermented intake were sustained, compared to baseline. Microbial diversity significantly increased within the HFF and control groups, especially in HFF participants over 50 (p = 0.04). Compared to CG, HFF showed no difference in microbial diversity, whereas the HDF group showed a significant decrease. The HDF intervention enhanced butyrogenic potential by increasing Anaerostipes, Faecalibacterium, and Bifidobacterium spp., and significantly reduced gastrointestinal transit time (p = 0.01). The intake of high fiber improved and sustained sleep quality (p = 0.03). The HFF intervention significantly increased blood immune markers including CD5, CD6 and CD8A (T-cell activation), IL-18R1 (inflammatory signaling) and SIRT2, a longevity-associated deacetylase (Q < 0.05), and induced a modest shift in the gut microbiota of participants over 50 years toward a composition characteristic of younger participants. These findings highlight distinct biological pathways through which dietary fibers and fermented foods modulate host physiology. This is the first randomized controlled nutritional intervention using a citizen science approach that demonstrates the feasibility and scientific value of engaging participants in healthier food choices.
Longevity Relevance Analysis
(4)
The paper claims that high-fiber and fermented-food diets can modulate gut microbiota and immune function, potentially influencing longevity-related biological pathways. The study explores dietary interventions that may address underlying mechanisms of aging through gut health and immune modulation, which are relevant to longevity research.
Lingling Wu, Xiang Zhu, Yanxia Liu ...
· Cellular Senescence
· Department of Bioengineering, Stanford University, Stanford, CA, 94305, USA.
· pubmed
Aging is a major risk factor for chronic diseases and cancer. Cellular aging, particularly in adult stem cells, offers a high-throughput framework for dissecting the molecular mechanisms of aging.
Aging is a major risk factor for chronic diseases and cancer. Cellular aging, particularly in adult stem cells, offers a high-throughput framework for dissecting the molecular mechanisms of aging.
Longevity Relevance Analysis
(4)
The paper claims to identify aging and inflammatory aging signatures through CRISPRi screens. This research is relevant as it aims to dissect the molecular mechanisms of aging, which could contribute to understanding and potentially addressing the root causes of aging.
Yichu Fu, Binhan Wang, Aqu Alu ...
· Signal Transduction
· College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
· pubmed
Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immun...
Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels. Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials. In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.
Longevity Relevance Analysis
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The paper discusses the mechanisms of immunosenescence and potential interventions to mitigate its effects on age-related diseases. This research is relevant as it addresses the underlying causes of aging-related immune dysfunction, which is crucial for developing strategies to promote longevity and improve healthspan.
Yi Xiang, Qiong Meng, Zitong Huang ...
· Aging
· School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
· pubmed
Biological aging is a heterogeneous process that varies across organs and systems. The dynamic hormonal changes during the menopausal transition may have profound and organ-specific impacts on biological aging. However, the relationship between the menopausal transition and both ...
Biological aging is a heterogeneous process that varies across organs and systems. The dynamic hormonal changes during the menopausal transition may have profound and organ-specific impacts on biological aging. However, the relationship between the menopausal transition and both comprehensive and organ-specific biological aging remains poorly understood. This study aimed to investigate the associations between menopausal factors and both comprehensive and organ-specific biological aging, as well as the modifying role of reproductive history.
Longevity Relevance Analysis
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The paper investigates the associations between menopausal factors and biological aging across multiple organ systems. This research is relevant as it explores the hormonal changes during menopause and their potential impact on biological aging, which aligns with understanding the mechanisms of aging and longevity.
Aurel Popa-Wagner, Dirk M Hermann, Thorsten R Doeppner ...
· Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
· Chair of Vascular Neurology and Dementia, Department of Neurology, University Hospital Essen, Essen, Germany.
· pubmed
Older individuals are typically more susceptible to stroke, and age-related differences in brain plasticity significantly affect recovery and treatment responses following cerebral ischemia and traumatic brain injury. Extracellular vesicles (EVs) have emerged as promising diagnos...
Older individuals are typically more susceptible to stroke, and age-related differences in brain plasticity significantly affect recovery and treatment responses following cerebral ischemia and traumatic brain injury. Extracellular vesicles (EVs) have emerged as promising diagnostic and therapeutic tools due to their role in intercellular communication and ability to cross the blood-brain barrier. While EVs hold potential in promoting brain repair, their efficacy is influenced by donor age-those derived from young stem cells exhibit more regenerative profiles, whereas aged donor EVs may carry senescence-related signals that impede recovery. Emerging therapies, including senolytics, exosome-based approaches, and immune modulation, aim to enhance post-stroke repair, yet a substantial translational gap persists, especially in adapting these strategies to the aged brain. Differences in immune responses, neurovascular integrity, and repair mechanisms between young and aged individuals further complicate therapeutic development. Incorporating aged animal models in preclinical research is thus essential for ensuring the relevance and safety of interventions in elderly patients. These findings underscore the need for age-tailored strategies that reflect the unique biological landscape of aging, paving the way for more effective treatments for stroke and related neurological conditions in older adults.
Longevity Relevance Analysis
(4)
The paper claims that age-related differences in neuroplasticity significantly affect recovery from stroke, and that extracellular vesicles derived from younger donors may enhance post-stroke repair in older individuals. This research is relevant as it addresses the biological mechanisms underlying aging and their implications for therapeutic strategies aimed at improving recovery in age-related conditions.
Nazma Malik, Reuben J Shaw
· Annual review of cell and developmental biology
· 1Metabolism in Immunity, Cancer & Aging Group, MRC Laboratory of Medical Sciences, Imperial College London, London, United Kingdom; email: [email protected].
· pubmed
Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of euk...
Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.
Longevity Relevance Analysis
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The paper claims that AMPK modulates mitochondrial health and metabolic adaptations. The focus on AMPK as a central regulator of energy metabolism and mitochondrial function is relevant to understanding the mechanisms of aging and potential interventions for longevity.
Najm Ul Hassan, William Kojo Smith, Hafiza Ayesha Nawaz ...
· Longevity
· Center for Circadian Clocks, Soochow University, Suzhou, China.
· pubmed
The desire to increase life expectancy, coupled with the decline in biological functions that occurs as we age, represents one of the most significant challenges facing our society. Age-related declines in biological functions contribute to frailty and morbidity, demanding innova...
The desire to increase life expectancy, coupled with the decline in biological functions that occurs as we age, represents one of the most significant challenges facing our society. Age-related declines in biological functions contribute to frailty and morbidity, demanding innovative strategies to promote healthy aging. The circadian clock, which controls daily physiological processes, is intricately linked to aging and overall health. Circadian disruptions can lead to metabolic dysfunction, impaired immune responses, increased DNA damage, and elevated disease susceptibility. On the other hand, maintaining robust circadian rhythms through interventions such as regular sleep-wake patterns, time-restricted feeding, and physical activity may extend health span and longevity. The circadian clock affects various molecular pathways associated with aging, including the insulin/IGF, mTOR, and sirtuin signaling pathways. Enhancing circadian rhythms presents a promising avenue for mitigating age-related disorders and promoting healthy aging. This review highlights the potential of circadian clock-based interventions as a transformative strategy to improve the quality of life and extend the healthspan of aging individuals.
Longevity Relevance Analysis
(4)
Resetting our circadian clock through various interventions may extend healthspan and longevity. The paper discusses the relationship between circadian rhythms and aging, focusing on how maintaining robust circadian rhythms can mitigate age-related disorders, which aligns with the goal of addressing the root causes of aging.
Shinji Nakamichi, Leo Yamada, Christopher Roselle ...
· GeroScience
· Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
· pubmed
Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while ...
Δ133p53α is a naturally occurring isoform of the tumor suppressor protein p53. Δ133p53α functions as a physiological dominant-negative inhibitor of the full-length p53 protein (commonly referred to as p53). Δ133p53α preferentially inhibits p53-mediated cellular senescence, while it does not inhibit, or may even promote, p53-mediated DNA repair. Owing to this selective inhibitory activity that preserves genome stability, Δ133p53α represents a promising target for enhancement in the prevention and treatment of diseases associated with increased senescence of normal cells. These diseases include Alzheimer's and other neurodegenerative diseases, premature aging diseases such as Hutchinson-Gilford progeria syndrome (HGPS), and idiopathic pulmonary fibrosis (IPF). Current cell-based therapies, which are limited by increased cellular senescence, may also benefit from Δ133p53α-mediated improvements. As an initial application of Δ133p53α in improving therapeutic cells, we here introduce Δ133p53α-armored chimeric antigen receptor (CAR)-T cells. Based on our previous and ongoing studies using various types of senescent human cells in vitro, we also discuss the importance of further exploring the therapeutic potentials of Δ133p53α, with particular focus on HGPS and IPF. The development of mouse models facilitates in vivo evaluation of the therapeutic effects of Δ133p53α, potentially leading to future clinical applications.
Longevity Relevance Analysis
(4)
The paper claims that Δ133p53α can enhance cancer immunotherapy and improve therapeutic approaches for diseases associated with cellular senescence. This research is relevant as it explores a potential mechanism to mitigate the effects of cellular senescence, which is a key contributor to aging and age-related diseases.
Amin Haghani, Ake T Lu, Qi Yan ...
· GeroScience
· Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. [email protected].
· pubmed
Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigeneti...
Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.
Longevity Relevance Analysis
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EnsembleAge demonstrates that integrating multiple epigenetic clocks can improve the assessment of biological aging and intervention effects. This paper is relevant as it addresses the root causes of aging by providing a robust tool for identifying and validating interventions that modulate biological aging.
Mishra, M., Kim, H.-H., Youm, Y.-H. ...
· physiology
· Yale School of Medicine
· biorxiv
Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower ...
Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.
Longevity Relevance Analysis
(5)
The paper claims that complement C3 deactivation is a metabolically regulated checkpoint that reduces inflammaging and can extend healthspan. This research is relevant as it addresses a potential mechanism underlying aging and healthspan extension through immunometabolic pathways, rather than merely treating age-related diseases.
Peng Li, Yi Yang, Xiang Qin ...
· Research (Washington, D.C.)
· Department of Anesthesiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
· pubmed
This perspective critically examines the paradigm-shifting findings regarding cellular senescence's dual role in tissue biology, particularly focusing on its unexpected regenerative potential in hair growth. While cellular senescence has traditionally been viewed as a detrimental...
This perspective critically examines the paradigm-shifting findings regarding cellular senescence's dual role in tissue biology, particularly focusing on its unexpected regenerative potential in hair growth. While cellular senescence has traditionally been viewed as a detrimental process associated with aging and tissue dysfunction, research has revealed its surprising beneficial effects on tissue regeneration. We analyze the groundbreaking discovery that senescent melanocytes can stimulate hair follicle stem cells through the osteopontin-CD44 signaling pathway, challenging the conventional understanding of senescence. This perspective also evaluates the implications of this finding for both basic research and therapeutic applications, suggesting that cellular senescence represents a complex, context-dependent phenomenon rather than a uniformly detrimental process. We discuss how this new perspective necessitates a more nuanced approach to senescence-targeted therapies and opens novel therapeutic possibilities for hair loss treatment. This analysis underscores the importance of understanding senescent cell heterogeneity and their diverse functions in tissue homeostasis, which could lead to more precise therapeutic strategies in regenerative medicine.
Longevity Relevance Analysis
(5)
Senescent melanocytes can stimulate hair follicle stem cells through the osteopontin-CD44 signaling pathway. This research challenges the traditional view of cellular senescence as solely detrimental and suggests that understanding its dual role could lead to novel therapeutic strategies in regenerative medicine, directly addressing mechanisms related to aging.
Shanshan Yao, Megan M Marron, Samaneh Farsijani ...
· Aging cell
· University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
· pubmed
Unintentional weight loss (UWL) is related to mortality and mobility limitation. Here, we aimed to develop a metabolite-based score for UWL and evaluate its prediction performance and explanation value for UWL-related health outcomes. Participants from the Health, Aging and Body ...
Unintentional weight loss (UWL) is related to mortality and mobility limitation. Here, we aimed to develop a metabolite-based score for UWL and evaluate its prediction performance and explanation value for UWL-related health outcomes. Participants from the Health, Aging and Body Composition (Health ABC) study with available metabolomics and valid follow-ups were included (N = 2286). First, in the derivation group (N = 1200), 27 of the 77 metabolites associated with incident UWL (> 3% annual UWL vs. weight stable) were selected by LASSO-logistic regression. The UWL metabolite score was calculated as a weighted sum of these 27 standardized metabolites, with higher scores indicating greater UWL risk. We then examined the standardized UWL metabolite score against all-cause mortality and incident mobility limitation using Cox regression. Overall, older adults with a one-SD higher UWL metabolite score had higher risks for mortality (1.44 [1.36, 1.52]) and mobility limitation (1.23 [1.15, 1.32]). The score also improved mortality prediction beyond traditional risk factors. Similar results were observed in the hold-out test group (n = 1086). Furthermore, this score explained 28% of the UWL-mortality relationship and 22% of the UWL-mobility limitation relationship beyond lifestyle and medical history, respectively. The score also predicted higher mortality and mobility limitation among those with intentional weight loss and weight gain, demonstrating a good Out-Of-Distribution generalizability. This metabolomic characterization of UWL is predictive of key aging outcomes in the Health ABC participants and captures a substantial portion of the mortality and mobility limitation risks related to unintentional weight loss, further validating the importance of these metabolite signatures.
Longevity Relevance Analysis
(4)
The paper claims that a metabolite score can predict mortality and mobility limitations associated with unintentional weight loss in older adults. This research is relevant as it explores biomarkers that may help identify and mitigate risks associated with aging, contributing to a better understanding of health outcomes in the elderly population.
Barbara Arbeithuber, Kate Anthony, Bonnie Higgins ...
· Oocytes
· Department of Gynaecology, Obstetrics and Gynaecological Endocrinology, Experimental Gynaecology and Obstetrics, Johannes Kepler University Linz, Linz 4040, Austria.
· pubmed
Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo ...
Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo mutations in single oocytes, blood, and saliva in women 20 to 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies were less prevalent in coding than noncoding regions, whereas mutations with low allele frequencies were more uniformly distributed along the mtDNA, suggesting frequency-dependent purifying selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations with aging and having functional consequences. These findings are particularly timely as humans tend to reproduce later in life.
Longevity Relevance Analysis
(4)
The paper claims that mitochondrial mutations do not increase with age in human oocytes, suggesting a protective mechanism against age-related accumulation. This research is relevant as it explores the underlying mechanisms of aging and reproductive health, which are critical for understanding longevity and the implications of delayed reproduction.
Offringa, R., Chouaref, J., Luden, T.
· plant biology
· Leiden University, Institute of Biology
· biorxiv
Members of the AT-HOOK MOTIF NUCLEAR LOCALIZED (AHL) gene family have been shown to play important roles in plant development. In Arabidopsis thaliana, one member of this family, AHL15, induces somatic embryogenesis and extends plant longevity when overexpressed - the latter thro...
Members of the AT-HOOK MOTIF NUCLEAR LOCALIZED (AHL) gene family have been shown to play important roles in plant development. In Arabidopsis thaliana, one member of this family, AHL15, induces somatic embryogenesis and extends plant longevity when overexpressed - the latter through strong repression of several ageing-related developmental transitions. However, its direct target genes and the mechanisms by which it regulates their expression have remained elusive to date. In this study we identified the genome-wide DNA binding sites of AHL15, and show that AHL15 binds throughout the genome at AT-rich sequences near the transcription start- and end sites in regions depleted of epigenetic marks. We show that induction of AHL15 activity causes strong and rapid changes in transcription, with the majority of the differentially expressed genes being downregulated but without directly affecting chromatin accessibility, resulting in developmental defects. In addition, AHL15 binding to regions near the transcription start and end sites was enhanced at genes that were differentially expressed upon AHL15 induction, and was especially strong near the transcription start site of upregulated genes and near the transcription end site of downregulated genes. Finally, we show that AHL15 shares binding sites with the chromatin architectural protein GH1-HMGA2/HON5, which was previously shown to alter transcription by disrupting gene loop formation. Together, our findings suggest that AHL15 affects the expression of its target genes by regulating the 3D organization rather than the accessibility of chromatin.
Longevity Relevance Analysis
(4)
AHL15 extends plant longevity by binding to chromatin and regulating gene expression. The study addresses mechanisms that could influence aging processes in plants, which is relevant to understanding longevity.
Diana C Hilpert, Muhammad Abdul Haseeb, Sharon E Bickel
· Molecular biology of the cell
· Department of Biological Sciences, Dartmouth College, 78 College St. Hanover, NH 03755.
· pubmed
Meiotic segregation errors in human oocytes are the leading cause of miscarriages and trisomic pregnancies and their frequency increases exponentially for women in their thirties. One factor that contributes to increased segregation errors in aging oocytes is premature loss of si...
Meiotic segregation errors in human oocytes are the leading cause of miscarriages and trisomic pregnancies and their frequency increases exponentially for women in their thirties. One factor that contributes to increased segregation errors in aging oocytes is premature loss of sister chromatid cohesion. However, the mechanisms underlying age-dependent deterioration of cohesion are not well-defined. Autophagy, a cellular degradation process critical for cellular homeostasis, is known to decline with age in various organisms and cell types. Here we quantify basal autophagy in Drosophila oocytes and use GAL4/UAS inducible knockdown to ask whether disruption of autophagy in prophase oocytes impacts the fidelity of chromosome segregation. We find that individual knockdown of autophagy proteins in Drosophila oocytes during meiotic prophase causes a significant increase in segregation errors. In addition, Atg8a knockdown in prophase oocytes leads to premature loss of arm cohesion and missegregation of recombinant homologs during meiosis I. Using an oocyte aging paradigm that we have previously described, we show that basal autophagy decreases significantly when Drosophila oocytes undergo aging. Our data support the model that a decline in autophagy during oocyte aging contributes to premature loss of meiotic cohesion and segregation errors.
Longevity Relevance Analysis
(4)
The paper claims that a decline in basal autophagy during oocyte aging contributes to premature loss of meiotic cohesion and segregation errors. This research is relevant as it investigates the mechanisms underlying age-related cellular processes, specifically how autophagy affects chromosome segregation in aging oocytes, which could provide insights into the root causes of reproductive aging.
Britton Scheuermann, Kathryn Nichol, Cathy Levenson ...
· The Journal of physiology
· Department of Kinesiology, Kansas State University, Manhattan, KS, USA.
· pubmed
The ageing global population is experiencing an increased prevalence of cerebrovascular diseases, such as stroke and dementia. This highlights a need for understanding the pathophysiological mechanisms of age-related cerebrovascular alterations, alongside benefits of intervention...
The ageing global population is experiencing an increased prevalence of cerebrovascular diseases, such as stroke and dementia. This highlights a need for understanding the pathophysiological mechanisms of age-related cerebrovascular alterations, alongside benefits of interventions such as physical activity. Therefore, our aims were to: (1) examine the impact of ageing and exercise training on cerebrovascular function and (2) to characterize age- and exercise training-related changes in the hippocampus transcriptome. Young and old male rats were randomized to a sedentary condition or exercise training for 10 weeks. In the first protocol, cerebral arteries were isolated to test vasomotor reactivity, quantify gene/protein expression and assess nitric oxide production. In the second protocol, anhedonia was assessed and hippocampal tissue collected for RNA-sequencing. Bioinformatic analyses (i.e. protein-protein interaction mapping) were performed. Ageing impaired endothelium-dependent vasoreactivity in the posterior communicating artery (PCoA), with a shift from endothelial nitric oxide synthase (NOS)- to neuronal NOS-mediated vasorelaxation, as well as alterations in oxidative stress production. In support, PCoA superoxide-mediated vasoreactivity and neuronal NOS-mediated production of NO decreased with age. Exercise enhanced vasodilatation in young rats, but the results suggested reduced cerebrovascular plasticity in older animals. In the second protocol, exercise training attenuated the age-related increase in anhedonia behaviour. Hippocampal RNA-sequencing revealed altered inflammatory and oxidative stress pathways with ageing that were mitigated by exercise training. Our findings underscore the complex interplay between vascular/neuronal factors in the ageing brain. Furthermore, these findings highlight the therapeutic potential of exercise in mitigating the adverse effects of ageing on cerebral health. KEY POINTS: Ageing is associated with increased risks of cerebrovascular disease and neurocognitive decline. Little is known about the underlying mechanisms involved in this process, limiting our ability to design appropriate interventions. Ageing is associated with alterations in cerebrovascular function, including possible changes in the mechanisms underlying vasomotor reactivity. Hippocampal RNA-seq revealed age-related alterations in neuronal, vascular, immune and oxidative-stress related signalling pathways. Exercise training may have mitigated many of these age-related changes, suggesting that enhancing physical activity may be a feasible means to preserve cerebral health in older individuals.
Longevity Relevance Analysis
(4)
Exercise training mitigates age-related cerebrovascular dysfunction and depressive behavior through alterations in the hippocampal transcriptome. The study addresses underlying mechanisms of age-related changes in cerebrovascular health and suggests interventions that could enhance longevity and quality of life in older populations.
Yohei Arai, Nicholas W Chavkin, Yuka Arai ...
· Cellular Senescence
· Cardiovascular Medicine, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
· pubmed
The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this cond...
The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this condition has been associated with various age-associated diseases and reduced lifespan. Therefore, we investigated the role of hematopoietic LOY in promoting cellular senescence, focusing on kidney disease because of its well-documented connection with aging and senescence. Herein, a prospective cohort study revealed that LOY in blood is associated with an increased incidence of kidney diseases. Analyses of transcriptional signatures in human kidneys found that immune cell LOY is enriched in patients with kidney disease and associated with greater amounts of cellular senescence. In male mice reconstituted with bone marrow lacking the Y chromosome, renal dysfunction was accompanied by senescent cell accumulation in models of kidney injury and advanced age. Treatment with a senolytic agent promoted senolysis and preferentially inhibited the progression of renal dysfunction in LOY mice. Hematopoietic LOY led to up-regulation of multiple immune inhibitory receptors, and treatment with the combination of antibodies targeting PD-1 (programmed cell death protein 1) and SIRPα (signal regulatory protein α) reduced senescent cell accumulation and rescued the renal pathology conferred by hematopoietic LOY in the kidney injury model. Collectively, these data indicate that hematopoietic LOY contributes to pathological conditions by impairing the clearance of senescent cells through up-regulation of immune checkpoint proteins.
Longevity Relevance Analysis
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Hematopoietic loss of the Y chromosome impairs senescent cell clearance and contributes to renal disease. The study addresses a potential root cause of aging-related diseases by exploring the mechanisms of cellular senescence and immune checkpoint regulation, which are critical in understanding and potentially mitigating age-associated morbidity.
Fei Jiang, Takeshi Tohgasaki, Mayuko Kami ...
· Elastin
· Department of Mechanical Engineering, Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Ube, Yamaguchi, 755-8611, Japan. [email protected].
· pubmed
Skin firmness and elasticity are largely determined by the dermal extracellular matrix, particularly the elastin fiber network. Age-related degradation of elastin alters its architecture, contributing to diminished skin resilience. However, the quantitative relationship between e...
Skin firmness and elasticity are largely determined by the dermal extracellular matrix, particularly the elastin fiber network. Age-related degradation of elastin alters its architecture, contributing to diminished skin resilience. However, the quantitative relationship between elastin fiber geometry and macroscopic skin firmness remains incompletely understood. In this study, we developed a novel computational framework integrating realistic 3D elastin fiber geometries-extracted from confocal microscopy images of human abdominal skin samples (Caucasian females, aged 38-78 years)-into a finite element (FE) model of the dermal matrix. The elastin networks were explicitly represented as beam elements within the FE domain. Unconfined compression simulations were conducted to evaluate skin's elastic resistance force and correlate it with quantified geometric parameters of the elastin networks. The results revealed a significant age-dependent decline in skin firmness, strongly associated with reductions in fiber diameter, fiber count, volume fraction, network connectivity (as indicated by increased fragmentation and reduced maximum cluster size), and the proportion of vertically oriented fibers. Among these, fiber count and maximum cluster size were the most important predictors of skin firmness. This study provides quantitative, mechanistic insights into how specific architectural alterations in elastin fibers directly impact the mechanical properties of aging skin. These findings emphasize the critical role of elastin network integrity and structural organization in maintaining skin function and offer a compelling rationale for therapeutic or cosmetic strategies aimed at preserving or restoring the elastin framework to maintain skin firmness.
Longevity Relevance Analysis
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The study quantitatively links age-related changes in elastin fiber architecture to declines in skin firmness. This research is relevant as it addresses the structural integrity of the dermal extracellular matrix, which is crucial for understanding the biological mechanisms of aging and potential interventions to maintain skin function.
Shiqi Hu, Zhenhua Li, Dashuai Zhu ...
· Advanced materials (Deerfield Beach, Fla.)
· Department of Biomedical Engineering, Columbia University, 3960 Broadway, New York, NY, 10032, USA.
· pubmed
Circulating extracellular vesicles (EVs) play a crucial role in mediating communication between different cell populations and organs, significantly influencing inflammation and vascular diseases. To evaluate the role of EVs in regulating senescence, small EVs isolated from umbil...
Circulating extracellular vesicles (EVs) play a crucial role in mediating communication between different cell populations and organs, significantly influencing inflammation and vascular diseases. To evaluate the role of EVs in regulating senescence, small EVs isolated from umbilical cord plasma (young sEVs, Y-sEVs) are compared with those from the plasma of elderly individuals (old sEVs, O-sEVs, >70 years old) to identify key cargo components. To investigate their effects on senescence, Y-sEVs or O-sEVs are administered to aged mice using transdermal microneedle patches, enabling sustained EV release into the circulation. Doxorubicin is administered to induce enhanced endothelial senescence in aged mice (22-24 months old). Single-cell RNA sequencing revealed that Y-sEV treatment downregulated senescence-related genes in endothelial cells decreased the proportion of activated fibroblasts in the heart, and reduced disease-associated microglia in the brain. Delivery of Y-sEVs via microneedle patches preserved endothelial cell function, and mitigated inflammation and senescence, whereas O-sEVs exacerbated endothelial dysfunction.
Longevity Relevance Analysis
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The paper claims that small extracellular vesicles from young blood can mitigate endothelial senescence in aged mice. This research addresses the underlying mechanisms of aging by exploring the potential of young sEVs to reverse age-related cellular dysfunction, which is directly relevant to longevity and age-related diseases.
Mamoru Oyabu, Tomoki Sato, Runa Kawaguchi ...
· Cell reports
· Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan; Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
· pubmed
Muscle wasting leads to reduced activities of daily living, an increased number of care-dependent individuals, and increased mortality. However, the metabolomic adaptations underlying muscle wasting remain poorly understood. Here, by comparing physiological, genetically induced, ...
Muscle wasting leads to reduced activities of daily living, an increased number of care-dependent individuals, and increased mortality. However, the metabolomic adaptations underlying muscle wasting remain poorly understood. Here, by comparing physiological, genetically induced, pathological, and age-related muscle atrophy, we identify the metabolites modulated by muscle atrophic stimuli, which we term "atrometabolites." Integrated metabolomics reveal that dysfunctional polyamine synthesis is a common feature of muscle atrophy. Mechanistically, we identify that adenosylmethionine decarboxylase 1 (Amd1) and Amd2 are important for maintaining polyamine metabolism and that downregulation of Amd1 and Amd2 is a trigger of myotube atrophy. Using skeletal muscle-specific FoxO triple-knockout mice, we find that FoxOs are required for immobilization-induced metabolomic remodeling and identify FoxO-dependent atrometabolites. This study comprehensively elucidates the molecular basis of muscle metabolomic adaptation and provides the datasets that will lead to the discovery of mechanisms underlying tissue adaptation to maintain homeostasis.
Longevity Relevance Analysis
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The paper identifies specific metabolites and mechanisms involved in muscle atrophy, suggesting potential targets for interventions that could mitigate age-related muscle wasting. The study addresses a fundamental aspect of muscle health that is crucial for maintaining function and quality of life in aging populations.
Deng, J., Wang, Z.
· bioinformatics
· City of Hope
· biorxiv
Premature senescence is essential for tissue remodeling. Myocardial infarction (MI) induces pathological cardiac remodeling through fibroblast-driven extracellular matrix (ECM) production. The role of senescence in MI-induced remodeling process remains elusive. Here we identify a...
Premature senescence is essential for tissue remodeling. Myocardial infarction (MI) induces pathological cardiac remodeling through fibroblast-driven extracellular matrix (ECM) production. The role of senescence in MI-induced remodeling process remains elusive. Here we identify a gradual increment number of senescent cells within the ischemic heart, peaking at day 7 post- MI, in both wild-type and p16Ink4a-CreERT2-mT/mG senescence reporter mice. Lineage tracing shows that senescent cells transition to non-senescent state within 4 weeks after MI. We perform single-nucleus (sn) Multiome and fluorescence-based spatial transcriptomics analyses to profile senescent cells. We next generate a reference (query dataset) based on SPiDER- {beta}Gal/p16-EGFP positivity and map it back to the snMultiome dataset. We then deconvolute senescent cells in the integrated dataset using multiple computational algorisms. Through these approaches, we reveal that fibroblasts and its subpopulation-late myofibroblasts (MF)-constitute a major proportion of senescent cells, which functionally reduce ECM production. Importantly, ischemia-induced senescent MF show less soluble collagen production compared to TGF-{beta}1- induced non-senescent MF in vitro. At the functional level, depletion of senescent cells in vivo augments fibrosis and worsens cardiac myopathy post-MI. Our findings highlight the transient nature of senescent cells in the heart and underscore the importance of dynamic regulation of senescent cells post-MI.
Longevity Relevance Analysis
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The paper claims that senescent cells in the heart transition to a non-senescent state post-myocardial infarction and that their depletion worsens cardiac myopathy. This research is relevant as it explores the role of cellular senescence in cardiac remodeling, which is a fundamental aspect of aging and age-related diseases.
Julian, T. H., Dou, H., Duan, J. ...
· ophthalmology
· The University of Manchester
· medrxiv
The eye is a recognised source of biomarkers for cardiovascular and neurodegenerative disease risk. Here, we characterise the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integ...
The eye is a recognised source of biomarkers for cardiovascular and neurodegenerative disease risk. Here, we characterise the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integrating physiological, radiomic, metabolomic, and genomic information. We trained adversarial autoencoders (Ret-AAE) to represent optical coherence tomography (OCT) images and colour fundus photographs as 256-dimensional embeddings. Ret-AAE derived embeddings were associated with a range of cardiovascular and neurodegenerative diseases, including ischaemic heart disease, cerebrovascular disease, Parkinsons disease, and dementia. Examining associations across diverse omics datasets, we provide evidence linking ophthalmic imaging features to neurological and cardiovascular anatomy and function, lipid metabolism, and gene sets associated with neurodegenerative pathology. Collectively, our findings demonstrate that ophthalmic features reflect complex, multisystem biological processes, and reinforce the role of the eye as a composite indicator of systemic health.
Longevity Relevance Analysis
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The paper claims that ophthalmic imaging features can serve as indicators of cardiovascular and neurodegenerative diseases through a multi-omic analysis. This research is relevant as it explores systemic health indicators that could potentially lead to a better understanding of aging processes and age-related diseases, although it primarily focuses on associations rather than addressing root causes of aging.
Jie Luo, Ling Chen, Xiaoxian Zhang ...
· Cell proliferation
· Cord Blood Bank Centre, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
· pubmed
Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we de...
Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we demonstrate that pioglitazone significantly mitigates mitochondrial reactive oxygen species (ROS) generation, lowers cyclooxygenase-2 (COX-2) mRNA levels, and rescues aberrant mitochondrial dynamics in vitro (increasing Opa-1 expression while decreasing Drp-1 expression). Furthermore, similar effects were observed with the selective Drp-1 inhibitor mdivi-1, suggesting that inhibiting mitochondrial fission mediates the therapeutic effects of pioglitazone. Pioglitazone administration activated AMPK phosphorylation, but these effects, along with pioglitazone's ability to reverse oxidative stress, inflammation, and mitochondrial fission, were abolished by the AMPK inhibitor compound C. In vivo, pioglitazone alleviated motor dysfunction, prolonged lifespan, and promoted weight gain in Ndufs4 KO mice. This was accompanied by enhanced mitochondrial fusion and increased levels of mitochondrial complex subunits. Consistently, pioglitazone attenuated neuroinflammation and oxidative stress in vivo. Collectively, our findings indicate that pioglitazone alleviates mitochondrial oxidative stress and inflammation through an AMPK-dependent inhibition of Drp-1-mediated mitochondrial fission. Therefore, suppression of mitochondrial fission may represent a novel therapeutic strategy for Leigh syndrome (LS).
Longevity Relevance Analysis
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Pioglitazone ameliorates mitochondrial oxidative stress and inflammation in Leigh syndrome through AMPK-dependent inhibition of mitochondrial fission. The paper addresses mitochondrial dysfunction, a key factor in aging and age-related diseases, suggesting a potential therapeutic strategy that could impact longevity.
Malcolm J Jackson
· Experimental physiology
· Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
· pubmed
Skeletal muscle adaptation to contractile activity is modulated by redox signalling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H
Skeletal muscle adaptation to contractile activity is modulated by redox signalling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H
Longevity Relevance Analysis
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The paper claims that redox signalling through reactive oxygen species modulates skeletal muscle adaptations to contractile activity. This research is relevant as it explores mechanisms that could address age-related muscle weakness, which is a significant aspect of aging and longevity.
Junhao Wen
· Nature aging
· Laboratory of AI and Biomedical Science (LABS), Department of Radiology, Columbia University, New York, NY, USA. [email protected].
· pubmed
Multi-organ biological aging clocks derived from clinical phenotypes and neuroimaging data have emerged as valuable tools for studying human aging and disease. Plasma proteomics provides an additional molecular dimension to enrich these clocks. In this study, I developed 11 multi...
Multi-organ biological aging clocks derived from clinical phenotypes and neuroimaging data have emerged as valuable tools for studying human aging and disease. Plasma proteomics provides an additional molecular dimension to enrich these clocks. In this study, I developed 11 multi-organ proteome-based biological age gaps (ProtBAGs) using 2,448 plasma proteins from 43,498 participants in the UK Biobank. Here I highlight methodological and clinical considerations for developing and using these clocks, including correction for age bias, organ specificity of proteins, sample size and underlying pathologies in the training data, which can affect model generalizability and clinical interpretability. In addition, I integrated 11 ProtBAGs with previously developed nine multi-organ phenotype-based biological age gaps to investigate genetic overlap and causal associations with disease endpoints. Finally, I show that incorporating features across organs improves predictions for systemic disease categories and all-cause mortality. These analyses provide methodological and clinical insights for developing and interpreting these clocks and highlight future avenues toward a multi-organ, multi-omics biological aging clock framework.
Longevity Relevance Analysis
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The study develops multi-organ proteome-based biological age gaps to improve predictions for systemic diseases and all-cause mortality. This research is relevant as it addresses biological aging clocks, which are crucial for understanding the mechanisms of aging and their implications for longevity and age-related diseases.
Lan Zhang, Yawei Liu, Zhijuan Hua ...
· Myocytes, Cardiac
· Department of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Hebei University, Baoding, China.
· pubmed
Cardiovascular aging is a key contributor to cardiovascular diseases (CVDs). As individuals age, the frequency and severity of cardiovascular events rise, establishing CVDs as a primary cause of death in older adults. Therefore, the development and exploration of drugs or bioacti...
Cardiovascular aging is a key contributor to cardiovascular diseases (CVDs). As individuals age, the frequency and severity of cardiovascular events rise, establishing CVDs as a primary cause of death in older adults. Therefore, the development and exploration of drugs or bioactive molecules that can effectively prevent cardiovascular aging and related diseases are urgently needed. This study evaluated the effects of salidroside, a key component of Rhodiola rosea extract, on cardiomyocyte senescence. We established an in vitro cardiomyocyte senescence model using D-gal/H
Longevity Relevance Analysis
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Salidroside activates the AMPK-mediated signaling pathway to alleviate cardiomyocyte senescence. This paper addresses a mechanism related to cardiovascular aging, which is a significant aspect of longevity research.
Yuxuan Jiang, Guo-Yang Li, Keshuai Hu ...
· Blood Pressure
· Institute of Biomechanics and Medical Engineering, AML, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China.
· pubmed
Arterial biomechanical indicators have long been recognized as fundamental contributors to the physiology and pathology of cardiovascular systems. Probing multiple biomechanical parameters of arteries simultaneously throughout the cardiac cycle is highly important but remains cha...
Arterial biomechanical indicators have long been recognized as fundamental contributors to the physiology and pathology of cardiovascular systems. Probing multiple biomechanical parameters of arteries simultaneously throughout the cardiac cycle is highly important but remains challenging. Here, we report a method to quantify arterial anisotropic stiffness, arterial wall stresses, and local blood pressure in a single measurement. With programmed ultrasound excitation and imaging, arterial axial and circumferential guided waves were simultaneously induced and measured in the longitudinal view. Then, a mechanical model was proposed to quantitatively predict the correlation of arterial guided waves with arterial biomechanical parameters. Our experimental design and biomechanical model enable an elastography method to assess temporal variations in blood pressure, bidirectional stiffness, and mechanical stresses in arterial walls. In vivo experiments were performed on healthy young, normotensive older, and hypertensive older volunteers. The results demonstrate that our method can find applications in understanding aging of cardiovascular system and diagnosis of cardiovascular diseases.
Longevity Relevance Analysis
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The paper presents a method to simultaneously measure arterial biomechanical parameters, which can enhance understanding of cardiovascular aging and disease. This research is relevant as it addresses the mechanical aspects of arterial health, which are crucial in the context of aging and longevity.
Chia-Heng Hsu, Yi-Jhan Li, Ting-Ni Guo ...
· Autophagy
· Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan.
· pubmed
Autophagic decline accompanies age and causes a deterioration in proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for macroautophagic/autophagic degradation and exocytosis. Loss of
Autophagic decline accompanies age and causes a deterioration in proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for macroautophagic/autophagic degradation and exocytosis. Loss of
Longevity Relevance Analysis
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Rab27 plays a crucial role in autophagic processes that may influence longevity and neuroprotection. The paper addresses mechanisms related to autophagy, which is a fundamental process in aging and longevity, suggesting potential pathways for intervention in age-related decline.