Seda Koyuncu, Yaiza Dominguez-Canterla, Rafael Alis ...
· Nature aging
· Institute for Integrated Stress Response Signaling, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. [email protected].
· pubmed
Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington's disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link t...
Aging is a major risk factor for neurodegenerative diseases associated with protein aggregation, including Huntington's disease and amyotrophic lateral sclerosis (ALS). Although these diseases involve different aggregation-prone proteins, their common late onset suggests a link to converging changes resulting from aging. In this study, we found that age-associated hyperactivation of EPS8/RAC signaling in Caenorhabditis elegans promotes the pathological aggregation of Huntington's disease-related polyglutamine repeats and ALS-associated mutant FUS and TDP-43 variants. Conversely, knockdown of eps-8 or RAC orthologs prevents protein aggregation and subsequent deficits in neuronal function during aging. Similarly, inhibiting EPS8 signaling reduces protein aggregation and neurodegeneration in human cell models. We further identify the deubiquitinating enzyme USP4 as a regulator of EPS8 ubiquitination and degradation in both worms and human cells. Notably, reducing USP-4 upregulation during aging prevents EPS-8 accumulation, extends longevity and attenuates disease-related changes. Our findings suggest that targeting EPS8 and its regulatory mechanisms could provide therapeutic strategies for age-related diseases.
Longevity Relevance Analysis
(5)
The paper claims that targeting EPS8 and its regulatory mechanisms can prevent protein aggregation and extend longevity. This research is relevant as it addresses the underlying mechanisms of aging and their connection to neurodegenerative diseases, suggesting potential therapeutic strategies for age-related conditions.
Qifeng Song, Shi Sun, Yuxiu Song ...
· Neural regeneration research
· Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, China.
· pubmed
Ferroptosis is a newly recognized form of programmed cell death characterized by iron overload-dependent lipid peroxidation. These pathological phenomena are often observed in neurodegenerative diseases. Aging is an irreversible process characterized by the deterioration of tissu...
Ferroptosis is a newly recognized form of programmed cell death characterized by iron overload-dependent lipid peroxidation. These pathological phenomena are often observed in neurodegenerative diseases. Aging is an irreversible process characterized by the deterioration of tissue and cell function. It has been shown to contribute to neurodegenerative diseases and increase susceptibility to ferroptosis. Therefore, ferroptosis may be involved in the progression of neurodegenerative diseases as a pathogenic factor, and aging is the common catalyst of both processes. The purpose of this review is to elucidate the latest progress on the mechanisms related to ferroptosis in neurodegenerative diseases, including iron overload, lipid peroxidation, antioxidant defense, cell membrane repair, and the regulation of autophagy and transcription factors. We also explored the relationship between ferroptosis and aging and reported that aging can induce ferroptosis by increasing iron overload, enhancing lipid peroxidation, and exacerbating autophagy disorders. Since ferroptosis is a pathogenic factor in neurodegenerative diseases, we screened gene bank databases and found that many genes associated with ferroptosis and neurodegenerative diseases overlap. Additionally, genes related to both the peroxidation pathway and ferroptosis are enriched. Ferroptosis occurs under conditions of age-related iron accumulation and lipid enrichment, as well as due to disorders in autophagy levels and transcription factors. Furthermore, in various neurodegenerative diseases, specific pathological changes or products can also contribute to the occurrence of ferroptosis. Finally, based on animal studies and clinical trials involving ferroptosis inhibitors, physical therapies, stem cell treatments, and exosome therapies in neurodegenerative diseases, it has been found that inhibiting ferroptosis can effectively reverse neurological dysfunction and cognitive impairment associated with these conditions. However, given various limitations, the conclusions of some animal studies and clinical trials have not been ideal, indicating that further large-scale research is necessary. Taken together, ferroptosis induces aging-related neurodegenerative diseases and neuronal cell death, triggering disease onset and progression. Ferroptosis inhibitors, physical therapies, stem cell treatments, and exosome therapies show great potential for inhibiting ferroptosis in neurodegenerative disease.
Longevity Relevance Analysis
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Ferroptosis is implicated as a pathogenic factor in neurodegenerative diseases, with aging acting as a catalyst for this process. The paper discusses mechanisms linking ferroptosis and aging, which are central to understanding and potentially addressing the root causes of age-related neurodegenerative diseases.
A Ibáñez de Opakua, R Conde, A de Diego ...
· npj metabolic health and disease
· ATLAS Molecular Pharma, Parque Tecnológico de Bizkaia, Ed. 800, 48160, Derio, Spain.
· pubmed
Molecular aging clocks estimate biological age from molecular biomarkers and often outperform chronological age in predicting health outcomes. Types include epigenetic, transcriptomic, proteomic, and metabolomic clocks. NMR-based metabolomic clocks provide a non-invasive, high-th...
Molecular aging clocks estimate biological age from molecular biomarkers and often outperform chronological age in predicting health outcomes. Types include epigenetic, transcriptomic, proteomic, and metabolomic clocks. NMR-based metabolomic clocks provide a non-invasive, high-throughput platform to assess metabolic health. We summarize key NMR-based models and present a new approach that combines high predictive accuracy with clinical interpretability, identifying disease-specific metabolic distortions and supporting risk stratification and early detection of accelerated aging.
Longevity Relevance Analysis
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The paper presents a novel NMR-based metabolomic approach for estimating biological age and identifying metabolic distortions related to aging. This research is relevant as it aims to improve the understanding of biological aging processes and offers potential for early detection and risk stratification, which are crucial for addressing the root causes of aging.
Ailsa M Jeffries, Tianxiong Yu, Jennifer S Ziegenfuss ...
· Nature
· Department of Molecular, Cell and Cancer Biology, Genome Integrity Program, University of Massachusetts Chan Medical School, Worcester, MA, USA.
· pubmed
Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process
Over time, cells in the brain and in the body accumulate damage, which contributes to the ageing process
Longevity Relevance Analysis
(4)
The paper investigates single-cell transcriptomic and genomic changes in the ageing human brain. This research is relevant as it explores the biological mechanisms underlying aging, which could contribute to understanding and potentially addressing the root causes of age-related decline.
Jiaxin Shi, Jason M Fletcher
· Population studies
· The Hong Kong University of Science and Technology.
· pubmed
Research indicates a significant slowdown in life expectancy growth in the United States (US) post 2010, marking a departure from the consistent progress in longevity throughout the twentieth century. We extend this understanding, tracing the deceleration of US life expectancy ba...
Research indicates a significant slowdown in life expectancy growth in the United States (US) post 2010, marking a departure from the consistent progress in longevity throughout the twentieth century. We extend this understanding, tracing the deceleration of US life expectancy back to the 1950s, after which average decadal change dropped from 3.80 to 1.61 years. Surprisingly, these mid-twentieth-century shifts were consistent across race and sex in the US and also in other high-income countries. Using a simple approach of quantifying potential life expectancy gains by eliminating mortality at specific ages, we find that the potential gains in life expectancy from reducing midlife mortality have been larger in the US than in other countries since 1900. The findings suggest that US life expectancy is unlikely to progress at the high speed observed between 1900 and the 1950s, with future advancements hinging on the reduction of old-age mortality, particularly from cardiovascular diseases and mental and nervous system diseases.
Longevity Relevance Analysis
(4)
The paper claims that potential life expectancy gains in the US from reducing midlife mortality have been larger than in other countries since 1900. This research is relevant as it addresses trends in life expectancy and explores factors that could influence future longevity advancements, focusing on mortality reduction rather than merely treating age-related diseases.
Bnaya Gross, Joseph Ehlert, Vadim N. Gladyshev ...
· q-bio.MN
· Not available
· arxiv
Despite the thousands of genes implicated in age-related phenotypes,
effective interventions for aging remain elusive, a lack of advance rooted in
the multifactorial nature of longevity and the functional interconnectedness of
the molecular components implicated in aging. Here, w...
Despite the thousands of genes implicated in age-related phenotypes,
effective interventions for aging remain elusive, a lack of advance rooted in
the multifactorial nature of longevity and the functional interconnectedness of
the molecular components implicated in aging. Here, we introduce a network
medicine framework that integrates 2,358 longevity-associated genes onto the
human interactome to identify existing drugs that can modulate aging processes.
We find that genes associated with each hallmark of aging form a connected
subgraph, or hallmark module, a discovery enabling us to measure the proximity
of 6,442 clinically approved or experimental compounds to each hallmark. We
then introduce a transcription-based metric, $pAGE$, which evaluates whether
the drug-induced expression shifts reinforce or counteract known age-related
expression changes. By integrating network proximity and $pAGE$, we identify
multiple drug repurposing candidate that not only target specific hallmarks but
act to reverse their aging-associated transcriptional changes. Our findings are
interpretable, revealing for each drug the molecular mechanisms through which
it modulates the hallmark, offering an experimentally falsifiable framework to
leverage genomic discoveries to accelerate drug repurposing for longevity.
Longevity Relevance Analysis
(5)
The paper claims to identify existing drugs that can modulate aging processes by leveraging a network medicine framework. This research is relevant as it addresses the root causes of aging by exploring drug repurposing to target hallmarks of aging, rather than merely treating age-related diseases.
Xie, G.
· bioinformatics
· Nantong University
· biorxiv
Aging Clock models have emerged as a crucial tool for measuring biological age, with significant implications for anti-aging interventions and disease risk assessment. However, human aging clock models that offer single-cell resolution and account for cell and tissue heterogeneit...
Aging Clock models have emerged as a crucial tool for measuring biological age, with significant implications for anti-aging interventions and disease risk assessment. However, human aging clock models that offer single-cell resolution and account for cell and tissue heterogeneities remain underdeveloped. This study introduces scAgeClock, a novel gated multi-head attention (GMA) neural network-based single-cell aging clock model. Leveraging a large-scale dataset of over 16 million single-cell transcriptome profiles from more than 40 human tissues and 400 cell types, scAgeClock demonstrates improved age prediction accuracy compared to baseline methods. Notably, the mean absolute error for the best-performing cell type is remarkably low at 2 years. Feature importance analysis reveals enrichment of aging clock genes related to ribosome, translation, defense response, viral life cycle, programmed cell death, and COVID-19 disease. A novel metric, the Aging Deviation Index (ADI) proposed by this study, revealed deceleration of ages in cells with higher differentiation potencies and tumor cells in higher phases or under metastasis, while acceleration of ages was observed in skin cells. Furthermore, scAgeClock is publicly available to facilitate future research and potential implementations.
Longevity Relevance Analysis
(5)
The paper claims to introduce scAgeClock, a single-cell aging clock model that improves age prediction accuracy and reveals insights into cellular aging dynamics. This research is relevant as it addresses the biological mechanisms of aging at a single-cell level, which could contribute to understanding and potentially mitigating the root causes of aging.
Fuentes-Ramos, M., Alaiz-Noya, M., Miozzo, F. ...
· neuroscience
· Instituto de Neurociencias (UMH-CSIC)
· biorxiv
While aging impairs memory precision, its effects on engram dynamics and gene expression remain poorly understood. To address this, we used TRAP2 activity-reporter mice, nuclear tagging, and FOS-based activity mapping to track neurons activated during contextual fear memory encod...
While aging impairs memory precision, its effects on engram dynamics and gene expression remain poorly understood. To address this, we used TRAP2 activity-reporter mice, nuclear tagging, and FOS-based activity mapping to track neurons activated during contextual fear memory encoding and reactivated during recall in young and aged mice. Across 378 brain regions, we quantified engram size, spatial distribution, and reactivation stability. We further applied fluorescence-activated nuclear sorting (FANS) combined with single-nucleus RNA sequencing (snRNA-seq) to characterize gene expression changes associated with memory encoding and recall across diverse cell types. In addition, we compared the transcriptional profiles of first-time versus second-time neuronal responder cells in the dentate gyrus. Aged brains exhibited altered engram allocation, reduced reactivation stability, and distinct gene expression patterns during memory retrieval. These findings reveal age-related changes in the organization and molecular identity of memory traces, providing mechanistic insight into cognitive decline and highlighting potential targets for intervention.
Longevity Relevance Analysis
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Aging alters the distribution, stability, and transcriptional signature of engram cells in the brain. This study provides insights into the mechanisms of cognitive decline associated with aging, which is directly relevant to understanding and potentially addressing the root causes of aging and age-related cognitive impairments.
Juan Long, Meng Ma, Yuting Chen ...
· eLife
· Department of Health Management and Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
· pubmed
The regulation of cellular metabolism and growth in response to nutrient availability is crucial for cell survival and can significantly impact on lifespan. Central to this regulation is a class of transporters that sense and transport specific nutrients and transduce the signal ...
The regulation of cellular metabolism and growth in response to nutrient availability is crucial for cell survival and can significantly impact on lifespan. Central to this regulation is a class of transporters that sense and transport specific nutrients and transduce the signal downstream to control genes responsible for growth and survival. In this study, we identified SUL1, a plasma membrane transporter responsible for regulating the entry of extracellular sulfate in
Longevity Relevance Analysis
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Deletion of sulfate transporter SUL1 extends yeast replicative lifespan via reduced PKA signaling instead of decreased sulfate uptake. The study explores a mechanism that could influence lifespan extension through metabolic regulation, which is directly related to the biology of aging.
Foley, J., McPherson, J., Roger, M. ...
· evolutionary biology
· University of Bristol
· biorxiv
Evolution has given rise to lifespans in extant species ranging from days to centuries. Given that mechanisms of ageing are highly conserved, studying long-lived lineages across the animal kingdom could yield insights relevant for healthy ageing in humans. However, typical models...
Evolution has given rise to lifespans in extant species ranging from days to centuries. Given that mechanisms of ageing are highly conserved, studying long-lived lineages across the animal kingdom could yield insights relevant for healthy ageing in humans. However, typical models of extended lifespan often live for decades, making them impractical for longitudinal studies. Ideal model systems would be organisms that are naturally long-lived compared to their close relatives, but have lifespans on experimentally tractable scales. Here, we present the Neotropical butterfly genus Heliconius as a novel model system for the evolution of extended longevity. We collate data from 27 species across the Heliconiini tribe to reveal a 25-fold variation in lifespan within the group, with our 348-day maximum for Heliconius hewitsoni longer than any butterfly species previously recorded in the scientific literature. While previous work has attributed this lifespan extension to a plastic response to enhanced nutrition, we conduct detailed survival and functional senescence analyses on two species representative of shorter- and longer-lived clades to show evidence of evolved, heritable mechanisms of slowed ageing in Heliconius. Our results add a new case study to the canon of noteworthy agers, and provide valuable insights into the evolution of increased longevity.
Longevity Relevance Analysis
(4)
The paper claims that the Heliconius butterfly genus exhibits evolved, heritable mechanisms of slowed ageing. This research is relevant as it explores the evolutionary basis of increased longevity and ageing mechanisms, which could provide insights into the biology of ageing and potential applications for lifespan extension.
Luciano, A., Robinson, L., Schott, W. H. ...
· genetics
· The Jackson Laboratory
· biorxiv
Research methods for the investigation of the biology of aging have often implicitly generalized strain-specific results. Dietary interventions, such as caloric restriction and periodic fasting, have been shown to enhance metabolic health and extend lifespan in preclinical models...
Research methods for the investigation of the biology of aging have often implicitly generalized strain-specific results. Dietary interventions, such as caloric restriction and periodic fasting, have been shown to enhance metabolic health and extend lifespan in preclinical models. However, inter-individual variation in physiological responses to these interventions, which affects their safety and efficacy when translated to humans, remains poorly understood despite being observed in multiple studies. In this study, we implemented intermittent fasting (IF) for two days per week in 10 inbred strains (n = 800 mice) from the Collaborative Cross (CC). The CC is a multiparent recombinant inbred strain panel that offers a diverse collection of reproducible models to study the genetic control of heterogeneous intervention responses. We conducted longitudinal phenotyping to characterize hundreds of traits, including lifespan, in the CC mice. We demonstrate that sex and genetic background induce variable responses to intermittent fasting across multiple physiological outcomes, including metabolic, hematologic, and immunologic health. Effects of IF on lifespan were sex-specific and variable across genetic backgrounds. Thus we establish that response to IF is genetically determined in an animal model with physiological features similar to humans. We compared our findings in the CC with those from a parallel study of Diversity Outbred (DO) mice, highlighting common predictors of health and lifespan, as well as key differences between the genetically diverse inbred and outbred models. These findings underscore the importance of genetic factors in dietary intervention responses, offering valuable insights for translating intermittent fasting benefits to human health and longevity.
Longevity Relevance Analysis
(4)
The paper claims that genetic background and sex influence the physiological responses to intermittent fasting, affecting lifespan outcomes. This research is relevant as it investigates the genetic regulation of dietary interventions that may enhance longevity and metabolic health, addressing fundamental aspects of aging biology.
Kun Zhang, Yehua Li, Yi Ren ...
· Aging cell
· Department of Histology and Developmental Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
· pubmed
Osteoporosis (OP) is a metabolic bone disease, characterized by loss of bone mass and destruction of bone microstructure, which has a high incidence of disability. Identification of the key factors of pathogenesis is essential for diagnosis and therapy. In this study, we have ide...
Osteoporosis (OP) is a metabolic bone disease, characterized by loss of bone mass and destruction of bone microstructure, which has a high incidence of disability. Identification of the key factors of pathogenesis is essential for diagnosis and therapy. In this study, we have identified the proton-sensing receptor GPR65, which is specifically expressed in osteoclasts and is significantly down-expressed in osteoclast differentiation, aging, ovariectomy (OVX)-, and tail suspension (TS)-induced osteoporotic bone tissue. In vivo experiments confirmed that knockout of GPR65 exacerbates bone loss and OP induced by TS, OVX, and aging. In vitro experiments demonstrated that silencing GPR65 or application of either endogenous or exogenous antagonist of GPR65 promotes osteoclast differentiation, whereas overexpression of GPR65 or application of either endogenous or exogenous agonist inhibits osteoclast differentiation, and knockout of Gpr65 mitigates this effect. Mechanistic studies revealed that GPR65 inhibits osteoclast differentiation by binding to Gαq, activating GSK3β, and suppressing its phosphorylation, thereby inhibiting the nuclear translocation of NFATc1 that mediates osteoclast differentiation. Furthermore, application of GPR65 agonist alleviated OVX-induced OP in vivo, indicating GPR65 as a novel therapeutic target for bone aging and OP.
Longevity Relevance Analysis
(4)
GPR65 functions as a key factor in osteoclast differentiation and bone aging, presenting it as a novel therapeutic target for osteoporosis. The study addresses a mechanism related to bone aging, which is a significant aspect of longevity research.
Jiale Cai, Deng Wu, Dahua Xu ...
· Cancer science
· College of Biomedical Information and Engineering, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou, China.
· pubmed
Cancer risk increases with age, and cellular senescence may be a major contributor to cellular carcinogenesis. Enormous efforts have been made to investigate the interrelation between aging and tumors, but little is known about the comparative features of normal aging, cellular s...
Cancer risk increases with age, and cellular senescence may be a major contributor to cellular carcinogenesis. Enormous efforts have been made to investigate the interrelation between aging and tumors, but little is known about the comparative features of normal aging, cellular senescence, and cancer at single-cell resolution. By integrating analyses of genomics, epigenomics, and bulk and single-cell transcriptomics, we revealed a directionally opposite transcriptional profile between cellular senescence and tumorigenesis at the single-cell level, which may be affected by epigenomic regulations. A total of 648 aging-dependent senescence-associated coregulated modules (SACMs), disproportionately affecting the reproductive systems of both females and males, were initially defined across 17 tissues. Single-cell analysis revealed that aging primarily affects endothelial cells, followed by T cells, epithelial cells, macrophages, and fibroblasts. Opposite directions of change in gene expression between aging and cancer can commonly be observed in endothelial, fibroblast, and epithelial cells, which may prompt the opposing patterns of gene expression between tissue aging and epithelial carcinoma at the bulk level. A similar pattern of expression can be observed in immune cells, which are characterized by decreased self-renewal with aging, but this pattern is reversed in epithelial carcinoma. Our study highlighted the role of senescence as a natural barrier against tumor formation and supported the idea that aging-related systemic environment changes create a protumorigenic milieu.
Longevity Relevance Analysis
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The study claims that aging and cancer exhibit directionally opposite transcriptional profiles at the single-cell level, suggesting that cellular senescence may act as a barrier to tumor formation. This paper is relevant as it explores the interplay between aging and cancer at a mechanistic level, addressing potential root causes of age-related diseases rather than merely treating symptoms.
Gutierrez, I., Edgar, C., Tyler, J. K.
· cell biology
· Weill Cornell Medicine
· biorxiv
Overexpression of the mRNA binding protein Ssd1 extends the yeast replicative lifespan. Using microfluidics to trap and image single cells throughout their lifespans, we find that lifespan extension by Ssd1 overexpression is accompanied by formation of cytoplasmic Ssd1 foci. The ...
Overexpression of the mRNA binding protein Ssd1 extends the yeast replicative lifespan. Using microfluidics to trap and image single cells throughout their lifespans, we find that lifespan extension by Ssd1 overexpression is accompanied by formation of cytoplasmic Ssd1 foci. The age-dependent Ssd1 foci are condensates that appear dynamically in a cell cycle-dependent manner and their failure to resolve during mitosis coincided with the end of lifespan. Ssd1 overexpression was epistatic with calorie restriction (CR) for lifespan extension and yeast overexpressing Ssd1 or undergoing CR were resistant to iron supplementation-induced lifespan shortening while their lifespans were reduced by iron chelation. The nuclear translocation of the Aft1 transcriptional regulator of the iron regulon occurred during aging in a manner that predicted remaining lifespan, but was prevented by CR. Accordingly, age-dependent induction of the Fit2 and Arn1 high-affinity iron transporters within the iron regulon was reduced by CR and Ssd1 overexpression. Consistent with age-dependent activation of the iron regulon, intracellular iron accumulated during aging but was prevented by CR and Ssd1 overexpression. Moreover, lifespan extension by Ssd1 overexpression or CR was epistatic to inactivation of the iron regulon. These studies reveal that CR and Ssd1 overexpression extend the yeast replicative lifespan by blocking deleterious age-dependent iron uptake, identifying novel therapeutic targets for lifespan extension.
Longevity Relevance Analysis
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Overexpression of Ssd1 and calorie restriction extend yeast replicative lifespan by preventing deleterious age-dependent iron uptake. The study addresses mechanisms of lifespan extension and identifies potential therapeutic targets related to aging processes, making it relevant to longevity research.
Ziyou Yuan, Eugenie Nepovimova, Qinghua Wu ...
· Biogerontology
· College of Life Science, Yangtze University, Jingzhou, 434025, China.
· pubmed
The circadian rhythm is a key biological mechanism that aligns organisms' physiological processes with Earth's 24-h light-dark cycle, crucial for cellular and tissue homeostasis. Disruption of this system is linked to accelerated aging and age-related diseases. Central to circadi...
The circadian rhythm is a key biological mechanism that aligns organisms' physiological processes with Earth's 24-h light-dark cycle, crucial for cellular and tissue homeostasis. Disruption of this system is linked to accelerated aging and age-related diseases. Central to circadian regulation is the CLOCK protein, which controls gene transcription related to tissue homeostasis, cellular senescence, and DNA repair. Research reveals CLOCK's dual role: in normal cells, it supports rejuvenation by activating DNA repair factors like XPA and modulating metabolism; in tumor cells, CLOCK signaling is often hijacked by oncogenic drivers like c-MYC and Pdia3, which inhibit telomere shortening / cellular senescence, thereby fostering uncontrolled proliferation and tumorigenesis. Additionally, gut microbiota-derived aryl hydrocarbon receptor (AhR) signals can disrupt the CLOCK-BMAL1 complex, affecting circadian rhythms. CLOCK also interacts with mTOR and NF-κB pathways to regulate autophagy and mitigate harmful secretions impacting tissue function. This review examines the molecular links between CLOCK and cellular senescence, drawing from animal and human studies, to highlight CLOCK's role in aging and its potential as a target for anti-aging therapies.
Longevity Relevance Analysis
(4)
The paper claims that CLOCK signaling plays a dual role in cellular senescence, influencing both rejuvenation in normal cells and tumorigenesis in cancer cells. This research is relevant as it explores the molecular mechanisms linking circadian rhythms to aging processes and cellular senescence, potentially identifying targets for anti-aging therapies.
Vijayraghavan Seshadri, Charmaine Chng, Joel Tyler ...
· Aging cell
· Monash Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, Victoria, Australia.
· pubmed
Cellular senescence is a state of irreversible cell cycle arrest accompanied by a distinctive inflammatory secretory profile known as the senescence-associated secretory phenotype (SASP). While various biomarkers, such as senescence-associated beta-galactosidase (SA-βgal), EdU in...
Cellular senescence is a state of irreversible cell cycle arrest accompanied by a distinctive inflammatory secretory profile known as the senescence-associated secretory phenotype (SASP). While various biomarkers, such as senescence-associated beta-galactosidase (SA-βgal), EdU incorporation, p21 and p16, are used to identify senescent cells, no single biomarker universally defines cellular senescence and current methods often fail to address heterogeneity in biomarker expression levels. This study leverages single-cell fluorescence imaging to assess multiple senescence markers including SA-βgal enzymatic activity, p21 and IL-6 expression and nuclear and cell area in chemotherapy-induced (mitomycin C) and oxidative stress-induced (D-galactose) senescence models in human fibroblasts. Our findings reveal significant heterogeneity in SA-βgal activity and distinct sub-populations within senescent cells. Nuclear and cell area measurements emerged as robust indicators of cellular senescence, displaying similar variability across individual cells. Importantly, we identified specific nuclear area sub-populations that strongly correlate with IL-6 expression levels, demonstrating a relationship between the heterogeneous expression of senescence biomarkers and the SASP. To address this heterogeneity, we introduced an induction threshold method to more accurately quantify the percentage of cells expressing senescence biomarkers. Furthermore, in both senescence models, we observed that rapamycin, a well-known senomorphic agent, selectively targets specific biomarker-expressing sub-populations. This study underscores the value of assessing cellular heterogeneity in senescence research and provides an improved approach for analysing senescence markers in diverse cellular contexts.
Longevity Relevance Analysis
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The study identifies heterogeneity in senescence biomarkers and demonstrates that rapamycin selectively targets specific sub-populations of senescent cells. This research is relevant as it addresses cellular senescence, a fundamental process associated with aging, and explores potential interventions that could influence longevity.
Chin, R., Zhang, X.-H., Anderson, K. M. ...
· neuroscience
· Yale University
· biorxiv
The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be e...
The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be established. Here, we examined the genetic associates of individual differences in diffusion-based measures of white matter in a population-based cohort (N=29,862) from the UK Biobank. Estimates of heritability from Genome-Wide Association Study (GWAS) data revealed that genetic factors are linked to population variability in 96.1% of 432 tract microstructural measures. The presence of shared genetic influences was observed to be greater within, relative to between, broad tract classes (commissural, association, projection, and complex cerebellar). Age associations with microstructural changes were estimated across diffusivity measures, with association class tracts showing the greatest vulnerability to age-related decline in older adults. Analyses of imputed cellular associates of age-related changes in white matter revealed a preferential relationship with cell gene markers of oligodendrocytes and other glial cell types, with sparse relationships observed for inhibitory and excitatory cells. These data indicate that white matter tract microstructure is shaped by genetic factors and suggest a role for glial cell-related transcripts in late-life changes in the structural wiring properties of the human brain.
Longevity Relevance Analysis
(4)
The paper claims that genetic factors and glial cell-related transcripts influence age-related changes in white matter microstructure. This research is relevant as it explores the genetic and cellular mechanisms underlying structural changes in the brain associated with aging, which could contribute to understanding the biological processes of aging and potential interventions.
Zhouwei Wu, Shu Yang, Zhichen Jiang ...
· Autophagy
· Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
· pubmed
Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucle...
Chaperone-mediated autophagy (CMA), a lysosome-dependent protein degradation pathway, plays a pivotal yet poorly understood role in cellular senescence-related degenerative diseases. Our study sheds light on a novel mechanism whereby UCHL1 plays a crucial role in mitigating nucleus pulposus cell (NPC) senescence and intervertebral disc degeneration (IVDD) by activating CMA to counteract autophagy-dependent ferroptosis. Through sequencing analysis of human samples, we identified UCHL1 as a potential factor influencing disc degeneration. Further research revealed that UCHL1 activates CMA by stabilizing HSPA8 through deubiquitination. HSPA8, in turn, recognizes and promotes the degradation of HPCAL1 via the CMA pathway by binding to its "KFERQ" motif, ultimately alleviating NPC senescence. Importantly, we demonstrated that engineered exosomes delivering
Longevity Relevance Analysis
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UCHL1 mitigates nucleus pulposus cell senescence by activating chaperone-mediated autophagy. The study addresses a mechanism related to cellular senescence and intervertebral disc degeneration, which are important aspects of aging and age-related degeneration.
Kim, Y. L., Jo, Y.-W., Yoo, T. ...
· developmental biology
· Seoul National University
· biorxiv
Muscle stem cells (MuSCs) are parenchymal cells in skeletal muscle regeneration and maintenance. With aging, MuSCs experience a decline in their regenerative function and reduction in their number. However, recent evidence points to substantial heterogeneity within the aged MuSC ...
Muscle stem cells (MuSCs) are parenchymal cells in skeletal muscle regeneration and maintenance. With aging, MuSCs experience a decline in their regenerative function and reduction in their number. However, recent evidence points to substantial heterogeneity within the aged MuSC population, raising questions about the underlying mechanisms of age-associated dysfunction. Here, we used Pax7CreERT2;RosaYFP mice (MuSCYFP) to label Pax7-expressing MuSCs and chronologically traced MusCs until geriatric age. Genetic labeling and chronological tracing revealed that the number of YFP+ MuSC remained comparable between young, middle and geriatric ages. At geriatric age, YFP+ MuSCs exhibited reduced expression of traditional MuSC markers such as VCAM1 and PAX7. A previously unrecognized subpopulation emerged, characterized by loss of VCAM1 and low or absent PAX7. Despite their altered marker profile, these cells retained transcriptional signatures of quiescence and myogenic potential, but displayed significantly reduced proliferative and regenerative capacities. They displayed gene expression patterns indicative of senescence-like state and were selectively ablated by senolytic treatment. DHT restored regenerative function in aged mice and re-induced VCAM1 expression in YFP+/Pax7-/low/VCAM1- cells, indicating responsiveness to rejuvenation. Based on their emergence with aging, functional impairment and responsiveness to rejuvenation, we termed this population GERI-MuSCs (Geriatric Emerging Rejuvenation-responsive and Impaired MuSCs). CD63 and CD200 were identified as novel surface markers that together with VCAM1, reliably detect GERI-MuSCs as well as classical Pax7+/VCAM1High MuSCs, providing a tool for comprehensive isolation of MuSCs from aged wild-type mice. Together, our findings provide a refined framework for studying MuSC aging and offer new tools for isolating functionally distinct MuSC subsets from aged skeletal muscle.
Longevity Relevance Analysis
(5)
The paper identifies a novel subpopulation of muscle stem cells (GERI-MuSCs) that exhibit age-related functional impairments and responsiveness to rejuvenation treatments. This research is relevant as it addresses the mechanisms of muscle stem cell aging, which is a root cause of age-related decline in muscle regeneration and function.
Shaokai Tang, Yuanwen Geng, Qinqin Lin
· Lipids in health and disease
· College of Sports Science, Jishou University, Jishou, 416000, China.
· pubmed
Aging is widely regarded as an irreversible arrest of cellular growth and proliferation, often accompanied by systemic metabolic organ abnormalities, ultimately reducing quality of life and increasing mortality in the elderly. Multi-organ transcriptomic analyses suggest that adip...
Aging is widely regarded as an irreversible arrest of cellular growth and proliferation, often accompanied by systemic metabolic organ abnormalities, ultimately reducing quality of life and increasing mortality in the elderly. Multi-organ transcriptomic analyses suggest that adipose tissue is among the earliest organs to respond to aging, characterized by changes in fat content and redistribution of adipose tissue, decline in thermogenic adipose function, reduced proliferation and differentiation capacity of adipose progenitor and stem cells, accumulation of senescent cells, and immunosenescence. These alterations may act synergistically and play a role in abnormalities in metabolic organs including the cardiovascular, liver, skeletal muscle, and brain. Studies have demonstrated that exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities by inhibiting inflammation, reducing the accumulation of ectopic lipids, enhancing the browning of white adipose tissue and thermogenesis in brown adipose tissue, improving lipid metabolism, regulating the secretion of adipokines, and mitigating immunosenescence. This review summarizes the main characteristics of adipose tissue aging, the effects of adipose tissue aging on metabolic organ abnormalities, and the potential mechanisms by which exercise ameliorates the effects of adipose tissue aging on metabolic organ abnormalities. It provides theoretical support for basic and clinical research on exercise-based prevention and treatment of aging-related diseases.
Longevity Relevance Analysis
(4)
Exercise interventions can mitigate the effects of adipose tissue aging on metabolic organ abnormalities. The paper addresses the mechanisms of adipose tissue aging and its impact on metabolic health, which are central to understanding and potentially reversing aspects of aging.
Lauren M Hablitz, Maiken Nedergaard
· The Journal of clinical investigation
· Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, New York, USA.
· pubmed
Cerebrospinal fluid dynamics play an important role in maintaining brain health and clearing metabolic waste from the brain. In this issue of the JCI, Gursky et al. investigate how CSF distribution is affected when its primary efflux pathway - the deep cervical lymph nodes - is d...
Cerebrospinal fluid dynamics play an important role in maintaining brain health and clearing metabolic waste from the brain. In this issue of the JCI, Gursky et al. investigate how CSF distribution is affected when its primary efflux pathway - the deep cervical lymph nodes - is disrupted by cauterization. This timely study reveals compensatory fluid drainage routes from the skull, age-dependent adaptations in CSF homeostasis, and the emergence of neuroinflammation when an efflux pathway is occluded. The findings underscore the need to better understand the physiological mechanisms governing CSF clearance, how these pathways evolve with aging, and whether CSF influx and efflux exhibit region-specific dynamics shaped by neuroanatomy. Additionally, the study raises important questions about whether peripheral injury can influence central nervous system states. A more complete understanding of CSF flow regulation may offer new perspectives on the origins of neuropathology.
Longevity Relevance Analysis
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Disruption of cerebrospinal fluid efflux pathways leads to compensatory drainage routes and neuroinflammation, highlighting the importance of CSF dynamics in brain health. The study addresses physiological mechanisms that could influence aging and age-related neurodegenerative processes, making it relevant to longevity research.
Andrew Patton, Jörn Davidsen
· PLoS computational biology
· Department of Physics and Astronomy, University of Calgary, Calgary, Alberta, Canada.
· pubmed
Although the brain's structural and functional alterations with age are individually well documented, how differences in cognitive abilities emerge from variations in the underlying spatio-temporal patterns of regional brain activity is largely unknown. Patterns of increased sync...
Although the brain's structural and functional alterations with age are individually well documented, how differences in cognitive abilities emerge from variations in the underlying spatio-temporal patterns of regional brain activity is largely unknown. Patterns of increased synchronization between brain regions are taken as enhanced cognitive integration, while decreased synchronization is indicative of cognitive segregation. The ability to dynamically switch between different levels of integration and segregation across different cognitive systems is believed to be crucial for overall cognitive performance. Building on a recently proposed cognitively informed, synchronization-based framework, we study here age-related variations in dynamical flexibility between segregation and integration, as captured by changes in the variable patterns of partial synchronization or chimera states. Leveraging personalized brain network models based on large-scale, multisite datasets of cross-sectional healthy cohorts, we systematically show how regional brain stimulation produces distinct patterns of synchronization. We find that chimera states play a crucial role in regulating the balance between cognitive integration and segregation as the brain ages, providing new insights into the mechanisms underlying cognitive decline and preservation in aging. Whereas the emergent synchronization behavior of brain regions belonging to the same cognitive system often show the same aging trends, different cognitive systems can demonstrate distinct trends. This supports the idea that aging affects cognitive systems differently and that understanding this variability is essential for a more comprehensive view of neuro-cognitive aging. At the same time, dynamical flexibility increases in the oldest age groups across most cognitive systems. This may reflect compensatory mechanisms to counteract age-related cognitive declines and points towards a phenomenon of dedifferentiation. Yet, the multiplicity of behaviors highlights that whereas dedifferentiation emerges in certain cognitive systems, differentiation can also occur in others. This illustrates that these processes, though seemingly oppositional, can coexist and unfold in parallel across different cognitive systems.
Longevity Relevance Analysis
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The paper claims that age-related variations in brain network synchronization patterns influence cognitive integration and segregation. This research is relevant as it explores the underlying mechanisms of cognitive decline and preservation in aging, contributing to a deeper understanding of neuro-cognitive aging processes.
Kevin Wilhelmsen, Aditi Deshpande, Sarah Tronnes ...
· NLR Family, Pyrin Domain-Containing 3 Protein
· BioAge Labs , Emeryville, CA, USA.
· pubmed
The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously perform...
The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously performed a DNA-encoded library screen to identify novel NLRP3-binding molecules. Herein we describe the characterization of BAL-0028 as a potent and specific inhibitor of NLRP3 signaling. Notably, BAL-0028 is a poor inhibitor of mouse NLRP3 but inhibits human and primate NLRP3 with nanomolar potency. Using cellular and biochemical analyses, we demonstrate that BAL-0028 binds to the NLRP3 NACHT domain at a site that is distinct from the MCC950-binding pocket. Using humanized NLRP3 mice, we show that a derivative of BAL-0028, BAL-0598, inhibits NLRP3 activation in vivo in a peritonitis model. Finally, we demonstrate that both BAL-0028 and BAL-0598 inhibit select hyperactive NLRP3 mutations associated with autoinflammatory diseases more potently than MCC950. BAL-0028 and BAL-0598 thus represent a new modality for NLRP3 inhibition in inflammatory diseases.
Longevity Relevance Analysis
(4)
The paper claims that BAL-0028 and its derivative BAL-0598 are potent inhibitors of the NLRP3 inflammasome, which is implicated in age-related inflammatory diseases. The relevance lies in its focus on a novel mechanism to inhibit NLRP3, potentially addressing a root cause of inflammation associated with aging and age-related diseases.
Emma B Hasselholm, Jesper Just, Simon Chang ...
· Klinefelter Syndrome
· Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark. [email protected].
· pubmed
The sex chromosome aneuploidies Turner syndrome (45,X; TS) and Klinefelter syndrome (47,XXY; KS) are associated with aging-related comorbidities, reduced life expectancy and genome-wide DNA methylation changes. This indicates that biological aging, reflecting physiological functi...
The sex chromosome aneuploidies Turner syndrome (45,X; TS) and Klinefelter syndrome (47,XXY; KS) are associated with aging-related comorbidities, reduced life expectancy and genome-wide DNA methylation changes. This indicates that biological aging, reflecting physiological function rather than chronological age, is increased in both syndromes. To investigate whether DNA methylation patterns linked to physiological decline could contribute to the comorbidity patterns and reduced lifespan in TS and KS, we applied so-called epigenetic clocks to DNA methylation data from cohorts of TS (n = 57) compared to female controls (n = 33) and KS (n = 65) compared to male controls (n = 63). Additionally, we evaluated correlations between epigenetic age and clinical variables, aiming to identify clinical aging markers in TS and KS.
Longevity Relevance Analysis
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The paper investigates the relationship between epigenetic age acceleration and clinical aging markers in Turner and Klinefelter syndromes. This research is relevant as it explores biological aging mechanisms and their implications for lifespan and health in specific genetic conditions, contributing to the understanding of aging processes.
Levy, T., Anselmi, C., Ishizuka, K. J. ...
· cell biology
· Stanford University
· biorxiv
Germline stem cells (GSCs), the source of gametes, are the only stem cells capable of passing genes to future generations and are therefore considered units of natural selection. Yet, the factors that influence GSC fitness, and thus govern GSC competition, which exist in both pro...
Germline stem cells (GSCs), the source of gametes, are the only stem cells capable of passing genes to future generations and are therefore considered units of natural selection. Yet, the factors that influence GSC fitness, and thus govern GSC competition, which exist in both protochordates and mammals, remain poorly understood. We studied how aging affects GSC fitness in the protochordate Botryllus schlosseri, an evolutionary crosspoint between invertebrates and vertebrates. GSCs were isolated and distinguished from developing and mature gametes using flow cytometry and scRNA-Seq, facilitated by a new PacBio genome assembly. Moreover, their function was validated through a novel lineage tracing approach that combines membrane-labeled GSC transplantation with scRNA-Seq. Leveraging our method to isolate them, single-cell transcriptomics showed significant age-related changes between young and old GSCs. Spermatids and sperm, however, showed minimal changes, suggesting that reproductive aging is governed by GSCs rather than by gametes. Reduced expressions of markers like DDX4 and PIWIL1 in aged GSCs mirrored trends in mammalian datasets, pointing to a conserved GSC-driven aging mechanism across chordate evolution. This study provides new techniques that lay the foundation to investigate further drivers of GSC fitness and highlights fertility-related genes as promising targets for therapies to preserve reproductive health.
Longevity Relevance Analysis
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Aging negatively impacts germline stem cell fitness, which may influence reproductive aging mechanisms. The study investigates the fundamental biological processes underlying aging in germline stem cells, which is crucial for understanding longevity and potential interventions in reproductive health.
Wei-Li Wang, Yu-Tsung Shih, Shu-Yi Wei ...
· Atherosclerosis
· Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli, Taiwan.
· pubmed
Aging is the foremost risk factor for metabolic syndrome and atherosclerosis, which is a principal cause of cardiovascular diseases (CVDs). Vascular endothelial cells (ECs), which line the vascular intima, play a central role in maintaining vascular homeostasis. Their dysfunction...
Aging is the foremost risk factor for metabolic syndrome and atherosclerosis, which is a principal cause of cardiovascular diseases (CVDs). Vascular endothelial cells (ECs), which line the vascular intima, play a central role in maintaining vascular homeostasis. Their dysfunction, marked by impaired barrier function, inflammation, and metabolic dysregulation, constitutes an early and pivotal event in atherogenesis. As key sensors of hemodynamic forces, ECs are constantly exposed to blood flow-induced shear stress, which exert divergent effects on metabolism depending on the flow pattern. Laminar flow with relatively high shear stress (LS), as a critical atheroprotective factor, maintains EC quiescence and promotes anti-inflammatory responses and antioxidant defense, whereas disturbed flow with low and oscillatory shear stress (OS), induces the athero-susceptible signaling network to activate glycolysis and inflammation in ECs. While genetic, epigenetic, and molecular signaling mechanisms in EC physiology and pathophysiology have been extensively explored, the crucial role of EC metabolism in EC dysfunction and atherogenesis remains largely understudied. By serving as precursors, intermediates, and end products of cellular processes, metabolites offer a dynamic snapshot of endothelial metabolic states under both physiological and pathophysiological conditions. With aging, ECs undergo profound metabolic reprogramming, including disrupted glycolysis, mitochondrial dysfunction, and altered redox homeostasis. In healthy vasculature, ECs maintain quiescence and metabolic homeostasis, primarily relying on glycolysis for energy. With aging, the gradual accumulation of atherosclerotic risk factors, including oxidative stress, inflammation, dyslipidemia, and hyperglycemia, drives metabolic reprogramming in ECs, particularly in regions exposed to disturbed flow with OS, ultimately leading to EC dysfunction and atherosclerosis. This review summarizes recent advances in age-related metabolic reprogramming in ECs and its contribution to atherosclerosis, particularly focusing on the dysregulation of glycolysis, fatty acid metabolism, amino acid metabolism, and mitochondrial respiration induced by age and fluid shear stress. This review also outlines recent methodologies for profiling EC metabolism, and discusses potential therapeutic applications of targeting EC metabolism to prevent or delay the development of atherosclerosis.
Longevity Relevance Analysis
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The paper claims that aging induces metabolic reprogramming in vascular endothelial cells, contributing to atherosclerosis development. This research addresses the underlying metabolic changes associated with aging, which are crucial for understanding and potentially mitigating age-related diseases.
Elsie Gonzalez-Hurtado, Claire Leveau, Keyi Li ...
· Nature aging
· Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
· pubmed
Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specifi...
Age-related inflammation or 'inflammaging' increases disease burden and controls lifespan. Adipose tissue macrophages (ATMs) are critical regulators of inflammaging; however, the mechanisms involved are not well understood in part because the molecular identities of niche-specific ATMs are unknown. Using intravascular labeling to exclude circulating myeloid cells followed by single-cell sequencing with orthogonal validation via multiparametric flow cytometry, we define sex-specific changes and diverse populations of resident ATMs through lifespan in mice. Aging led to depletion of vessel-associated macrophages, expansion of lipid-associated macrophages and emergence of a unique subset of CD38
Longevity Relevance Analysis
(4)
The paper claims that nerve-associated macrophages play a crucial role in regulating adipose homeostasis and controlling age-related inflammation. This research is relevant as it addresses mechanisms underlying inflammaging, which is a significant factor in aging and age-related diseases.
Xiao-Ting Yu, Nan Zhao, Yu-Tao Ma ...
· Acta pharmacologica Sinica
· Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Capital Medical University; Key Laboratory of Remodeling-Related Cardiovascular Diseases, Ministry of Education, Beijing, 100069, China.
· pubmed
Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for ma...
Progressive loss of vascular smooth muscle cells (VSMCs) is the pathophysiological basis for aortic aneurysm and dissection (AAD), a life-threatening disease, but the underlying mechanisms are largely unknown. Sirtuin 6 (SIRT6), a class III histone deacetylase, is critical for maintenance of VSMC homeostasis and prevention of vascular remodeling-related diseases. In this study, we investigated the role of VSMC SIRT6 in AAD and the molecular mechanism. We showed that the expression levels of SIRT6 were significantly reduced in VSMCs of the thoracic aorta in AAD patients. We constructed a VSMC-specific Sirt6 deficient mouse line and found that loss of Sirt6 in VSMCs dramatically accelerated angiotensin II (Ang II)-induced AAD formation and rupture, even without an Apoe-deficient background. In human aortic smooth muscle cells (HASMCs), knockdown of SIRT6 led to mitochondrial dysfunction and accelerated VSMC senescence. We revealed that SIRT6 bound to and deacetylated NRF2, a key transcription factor for mitochondrial biogenesis. However, Sirt6 deficiency inhibited NRF2 and reduced mRNAs encoding mitochondrial complex proteins. Notably, MDL-811, a newly developed small-molecule SIRT6 agonist, effectively reversed Ang II-induced mitochondrial dysfunction in HASMCs. In a BAPN-induced TAAD mouse model, administration of MDL-811 (20 mg/kg, i.p., every other day for 28 d) effectively mitigated AAD progression and reduced mortality. These results suggest that SIRT6 plays a protective role against AAD development, and targeting SIRT6 with small-molecule activators such as MDL-811 could represent a promising therapeutic strategy for AAD.
Longevity Relevance Analysis
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SIRT6 plays a protective role against thoracic aortic aneurysm development by maintaining mitochondrial homeostasis in vascular smooth muscle cells. The study addresses a mechanism related to cellular aging and dysfunction, which is pertinent to longevity research.
Stefania Lucia, Silvia Fornaro, Massimo Federici ...
· Acta diabetologica
· Neuroscience Area, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy. [email protected].
· pubmed
The growing prevalence of type 2 diabetes (T2D) among older adults represents a major public health concern, given its association with accelerated cognitive decline and increased risk of neurodegenerative diseases. Several diabetes-related mechanisms, including chronic hyperglyc...
The growing prevalence of type 2 diabetes (T2D) among older adults represents a major public health concern, given its association with accelerated cognitive decline and increased risk of neurodegenerative diseases. Several diabetes-related mechanisms, including chronic hyperglycaemia, oxidative stress, vascular dysfunction, and insulin resistance in the brain, negatively impact key cognitive domains, including memory and executive functions. These neuropathophysiological alterations are also linked to structural brain changes, contributing to vulnerability to dementia. This narrative review examines both established and emerging strategies aimed at counteracting the cognitive impact of T2D in aging populations. Traditional interventions, especially structured physical activity programs, have consistently demonstrated benefits for global cognitive functioning. In parallel, new pharmacological treatments, such as GLP-1 receptor agonists (e.g., semaglutide), not only improve glycemic control but may also exert neuroprotective effects. Multidomain approaches integrating metabolic management, nutritional optimization, physical exercise, and social engagement, such as those tested in the J-MIND-Diabetes study, have yielded promising outcomes in preserving cognitive functions. We argue that combining pharmacological and behavioral strategies holds significant potential for supporting cognitive health in elderly individuals with T2D. Such multimodal interventions may enhance resilience to cognitive decline, improve quality of life, and promote healthy brain aging in this at-risk population.
Longevity Relevance Analysis
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Combining pharmacological and behavioral strategies may enhance cognitive health in elderly individuals with type 2 diabetes. The paper addresses the cognitive decline associated with type 2 diabetes in aging populations and explores multidimensional approaches to mitigate this decline, which is relevant to longevity and age-related cognitive health.
Fernandes, S. A., Pan, J., Terziyska, D. S. ...
· cell biology
· Max Planck Institute for Biology of Ageing (MPI-AGE)
· biorxiv
Proper control of mTOR (mechanistic/mammalian target of rapamycin) signaling is relevant for health, disease and ageing. Information from intra- and extra-cellular signaling cues is transmitted to mTOR through an intricate signaling network that impinges on the Rag and Rheb GTPas...
Proper control of mTOR (mechanistic/mammalian target of rapamycin) signaling is relevant for health, disease and ageing. Information from intra- and extra-cellular signaling cues is transmitted to mTOR through an intricate signaling network that impinges on the Rag and Rheb GTPases to regulate its localization and activity. Interestingly, although mTOR is a heavily ubiquitinated protein, the role of this post-translational modification (PTM) in regulating its activation status remains poorly understood. Here, through an unbiased RNAi screen, we identified the tumor suppressor CYLD deubiquitinase (DUB) as a direct negative regulator of both mTORC1 and mTORC2 activities. Mechanistically, CYLD interacts with mTOR and removes non-degradative, K63-linked ubiquitin (Ub) chains from multiple of its residues. Consequently, CYLD loss-of-function cells are characterized by mTORC1/2 hyperactivation, elevated rates of protein synthesis, increased cell size, and resistance to serum-starvation-induced activation of cell death pathways. Moreover, silencing of cyld-1, the C. elegans CYLD ortholog, fully reverses the extended lifespan of low-TORC1-activity mutant worms. Finally, we find that inactivation of CYLD is associated with hyperactivation of mTORC1 also in skin biopsies from CYLD cutaneous syndrome (CCS) patients. In sum, our findings highlight CYLD as a sentinel of mTOR hyperactivation via direct control of its ubiquitination, and suggest that dysregulated mTOR activity may contribute to the development and progression of CCS tumors.
Longevity Relevance Analysis
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The paper claims that the tumor suppressor CYLD acts as a deubiquitinase for mTOR, negatively regulating its activity and influencing lifespan in C. elegans. The findings suggest a mechanism by which mTOR hyperactivation can be controlled, linking it to longevity and age-related processes.
Lopez-Pernas, G., Murga, M., Ahmed, W. ...
· cancer biology
· CNIO
· biorxiv
The one-two-punch approach refers to the sequential administration of two different chemotherapies, the second of which targets cancer cells that resisted the initial treatment. To find such a second punch, we performed a chemical screen to find drugs that are preferentially toxi...
The one-two-punch approach refers to the sequential administration of two different chemotherapies, the second of which targets cancer cells that resisted the initial treatment. To find such a second punch, we performed a chemical screen to find drugs that are preferentially toxic for cells with an activated DNA damage response (DDR). This screen identified the tyrosine kinase inhibitor GNF-7 as a top hit. Subsequent work revealed that GNF-7 is a potent senolytic, even when senescence is triggered by therapies that do not activate the DDR. Consistently, GNF-7 is highly efficacious to kill cancer cells previously treated with CDK4/6 inhibitors, including in patient-derived organoids and mouse xenografts. Surprisingly, the senolytic effect of GNF-7 is not mediated by the inhibition of a tyrosine kinase (TK), but rather by the activation of GCN2, an effect previously reported for other TK inhibitors. Together, our study reports the discovery of a novel senolytic agent that strongly synergizes with CDK4/6 inhibitors when applied sequentially and expands our understanding of the mechanisms behind the anticancer effects of TK inhibitors.
Longevity Relevance Analysis
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GNF-7 is identified as a novel senolytic agent that targets senescent cells through the activation of GCN2. The paper is relevant as it explores a potential therapeutic approach to eliminate senescent cells, which are implicated in aging and age-related diseases, thereby addressing a root cause of aging rather than merely treating symptoms.
Mingzhuang Hou, Yifan Ma, Yaoge Deng ...
· Proceedings of the National Academy of Sciences of the United States of America
· Department of Orthopaedics, First Affiliated Hospital of Soochow University, Suzhou 215006, China.
· pubmed
Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondr...
Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce fragmentation, and preserve mitochondrial function in chondrocytes. Specifically, SIRT3 directly deacetylates and indirectly deubiquitinates MFN2, preventing its degradation. MFN2-mediated mitochondrial-endoplasmic reticulum (ER) junctions support cellular homeostasis, alleviate ER stress, and maintain mitochondrial calcium ion balance, which collectively mitigate chondrocyte senescence. Extracellular vesicles engineered with MFN2 mRNA effectively prevented cartilage degeneration and restored mobility in osteoarthritic mice. These findings suggest that targeting MFN2 is a promising strategy to prevent cartilage degeneration and alleviate progression of osteoarthritis.
Longevity Relevance Analysis
(4)
The paper claims that targeting mitofusin-2 (MFN2) can restore mitochondrial function and prevent cartilage degeneration in osteoarthritis. This research addresses mitochondrial dysfunction, a key aspect of aging, and proposes a potential therapeutic strategy that could mitigate age-related degeneration in joint health.
Herzog, C. M. S., Vavourakis, C. D., Redl, E. ...
· systems biology
· Universitaet Innsbruck
· biorxiv
Extending human healthspan requires understanding how lifestyle interventions impact molecular systems across tissues and time. Here, we present the TirolGESUND Lifestyle Atlas (ClinicalTrials.gov: NCT05678426), a longitudinal, multi-modal resource profiling 156 healthy women (ag...
Extending human healthspan requires understanding how lifestyle interventions impact molecular systems across tissues and time. Here, we present the TirolGESUND Lifestyle Atlas (ClinicalTrials.gov: NCT05678426), a longitudinal, multi-modal resource profiling 156 healthy women (aged 30-60 years) undergoing 6-month intermittent fasting (n=114) or smoking cessation (n=42) interventions. Participants were sampled up to four times across seven tissues and fluids, generating >3,450 biospecimens with harmonised DNA methylation, metabolomics, microbiome, and immune profiling, alongside skin histology, barrier measurements, and rich clinical metadata. We demonstrate the utility of this dataset through: (i) multi-omics-wide association studies linking traits to molecular features; (ii) integrative factor modelling revealing coordinated cross-tissue signatures; (iii) epigenetic-biomarker cross-omic associations, and (iv) CpG-level variance decomposition mapping stable, individual-specific, tissue-restricted, and intervention-responsive methylation patterns. We further show that ageing-linked features are selectively malleable: highly compliant intermittent fasting participants exhibited attenuated or even age-opposing molecular trajectories within six months. The atlas enables unprecedented within-cohort comparisons across omic layers and tissues, supporting discovery of context-dependent biomarkers, cross-system coordination, and intervention responsiveness. Data are available via an interactive portal, with sensitive data under controlled access (https://eutops.github.io/lifestyle-atlas/). This resource provides a foundation for exploring biomarker association and multi-tissue epigenetics, enabling hypothesis generation and benchmarking for systems biology and human healthspan research.
Longevity Relevance Analysis
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The paper claims that highly compliant intermittent fasting participants exhibit age-opposing molecular trajectories within six months. This research is relevant as it explores lifestyle interventions that may directly influence the biological mechanisms of aging, contributing to the understanding of healthspan extension.
Thalida Em Arpawong, Belinda Hernandez, Claire Potter ...
· GeroScience
· Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA. [email protected].
· pubmed
The complexity of epigenetic changes that accompany aging has been distilled into a number of molecular timepieces-termed epigenetic clocks-that characterize the pace of biological aging to differing degrees. Here, we develop and validate a DNA methylation-based Physiological hea...
The complexity of epigenetic changes that accompany aging has been distilled into a number of molecular timepieces-termed epigenetic clocks-that characterize the pace of biological aging to differing degrees. Here, we develop and validate a DNA methylation-based Physiological health Age (PhysAge) score, comprised of eight DNA methylation surrogates to represent multi-system physiology and developed from commonly measured clinical biomarkers: CRP, peak flow, pulse pressure, HDL-cholesterol, Hba1c, waist-to-height ratio (WHR), cystatin C, and dehydroepianrosterone sulphate (DHEAS). We use data from the population-representative US Health and Retirement Study (HRS), split into a training (n = 1589) and test sample (n = 1588) and corroborate findings in two independent cohorts: The Irish Longitudinal Study of Aging (TILDA; n = 488) and the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA; n = 1830). PhysAge and the predominant second-generation epigenetic clocks, PhenoAge, GrimAge2, and DunedinPACE, were tested for their prediction of mortality and multiple age-related clinical measures (i.e., grip strength, gait speed, cognitive function, disability, frailty). PhysAge was comparable to extant clocks in predicting health measures and was indistinguishable from GrimAge2 in predicting mortality, despite not being trained on mortality. Moreover, the eight individual surrogates comprising PhysAge predicted health outcomes better than the measured values in many instances. The established clinical relevance of the biomarkers from which surrogates were derived opens up new opportunities for cross-study and cross-country comparisons of population health. Findings suggest that the DNA methylation PhysAge can be leveraged as a single biomarker to represent multiple physiological systems and offers utility in the context of clinical monitoring.
Longevity Relevance Analysis
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The paper claims that the DNA methylation-based Physiological health Age (PhysAge) score can predict health outcomes and mortality in older adults. This research is relevant as it addresses biological aging through a novel multi-system approach, potentially offering insights into the root causes of aging and improving health monitoring in older populations.
Lu, Y. R., Cameron, J. C., Hu, Y. ...
· genetics
· Whitehead Institute for Biomedical Research
· biorxiv
Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration ...
Oct4, Sox2, and Klf4 (OSK) Yamanaka factors induce pluripotency and reverse age-related epigenetic changes, yet the mechanisms by which they promote rejuvenation remain poorly explored. Oxidative stress contributes to CNS aging and retinal pigmented epithelium (RPE) degeneration in age-related macular degeneration. We find that OSK expression in RPE restores retinal structure and visual function in aged mice and promotes oxidative resilience through a non-canonical, Tet2-independent pathway. Integrative functional genomics identifies GSTA4, a detoxifying enzyme that clears the lipid peroxidation byproduct 4-HNE, as a necessary and sufficient OSK effector. Dynamic GSTA4 regulation by OSK recapitulates a stem cell derived stress resilience program. GSTA4 overexpression alone enhances mitochondrial resilience, rejuvenates the aged RPE transcriptome, and reverses visual decline. GSTA4 is consistently upregulated across diverse lifespan-extending interventions suggesting a broader pro-longevity role. These findings uncover a previously unrecognized protective axis driven by Yamanaka factors that circumvents reprogramming, providing therapeutic insights for age-related diseases.
Longevity Relevance Analysis
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The paper claims that OSK factors activate a non-canonical oxidative resilience pathway that rejuvenates retinal pigmented epithelium and restores vision in aged mice. This research addresses mechanisms of rejuvenation and oxidative stress resilience, which are central to understanding and potentially mitigating age-related degeneration.
Maria Grazia Perino, Miguel Calvo-Rubio Barrera, Daniel R Riordon ...
· GeroScience
· Laboratory of Cardiovascular Science, Intramural Research Program, National Institute On Aging, National Institutes of Health, 251 Bayview Blvd, Baltimore, MD, 21224, USA. [email protected].
· pubmed
Dysregulated proteostasis is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic-adenosine-monophosphate (cAMP)-dependent stress change with aging in mice harboring marked cardiac-specific over-expression of adenylyl cyclase VII...
Dysregulated proteostasis is a hallmark of aging. We investigated how efficiently proteostatic adaptations to chronic cardiac cyclic-adenosine-monophosphate (cAMP)-dependent stress change with aging in mice harboring marked cardiac-specific over-expression of adenylyl cyclase VIII (TG
Longevity Relevance Analysis
(4)
The paper claims that the failure of cardiac proteostatic adaptations to chronic cAMP-stress accelerates heart aging. This research addresses the mechanisms of aging at the cellular level, specifically focusing on proteostasis in the context of heart aging, which is directly relevant to understanding and potentially mitigating age-related decline.
Hiebert, L. S., Soesbe, A., Cui, Q. ...
· evolutionary biology
· University of California Santa Barbara
· biorxiv
While most knowledge of animal DNA methylation comes from vertebrates, this epigenetic mark remains poorly understood in invertebrates, which comprise the majority of animal diversity. For instance, how promoter and gene body methylation contribute to gene regulation, and how met...
While most knowledge of animal DNA methylation comes from vertebrates, this epigenetic mark remains poorly understood in invertebrates, which comprise the majority of animal diversity. For instance, how promoter and gene body methylation contribute to gene regulation, and how methylation relates to aging, are still relatively unknown in most invertebrates. Focusing on the California mussel (Mytilus californianus), we paired whole-genome resequencing and whole-genome bisulfite sequencing from the same individuals and evaluated relationships among promoter methylation, gene body methylation, gene expression, and age. Using seven individuals spanning a range of body sizes from the Santa Barbara Channel, California, we found standing genetic variation levels similar to related species and a relatively small effective population size. CpG methylation was enriched in gene bodies, and gene body methylation was positively associated with expression. Promoter methylation was less frequent but showed a strong negative association with expression and remained the best predictor of repression after accounting for gene body methylation, aligning with patterns widely documented in vertebrates and adding to the limited evidence in invertebrates that promoter methylation can be regulatory. We identified thousands of age-associated differentially methylated loci with directional changes across age classes, providing candidate sites for epigenetic clocks that could enable assessment of biological age, health, and stress resilience in wild and cultured populations.
Longevity Relevance Analysis
(4)
The paper claims that promoter methylation is a key regulatory mechanism in gene expression and is associated with aging in the California mussel. This research contributes to understanding the epigenetic factors influencing aging, which is relevant to the root causes of longevity and biological age assessment.
Calvo-Asensio, I., Tarcevski, A., Dhalla, F. ...
· immunology
· Institute of Medical Sciences, University of Aberdeen
· biorxiv
The thymus is a primary lymphoid organ which provides essential structural and functional support for the development of naive T cells. Thymic epithelial cells (TECs), key components of the thymic stroma, are classified into cortical (cTEC) and medullary (mTEC) lineages based on ...
The thymus is a primary lymphoid organ which provides essential structural and functional support for the development of naive T cells. Thymic epithelial cells (TECs), key components of the thymic stroma, are classified into cortical (cTEC) and medullary (mTEC) lineages based on their distinct molecular, structural, transcriptional, and functional characteristics. Advances in single-cell RNA sequencing (scRNA-seq) have revealed significant TEC heterogeneity, including the identification of intertypical TECs that share properties of both cTEC and mTEC and have been postulated to play a role in the development and maintenance of thymic function. To date, the identity and maintenance of postnatal TEPCs remain unclear, with debates on whether bipotent TEPCs persist after birth or if lineage-restricted progenitors independently maintain TEC compartments. Using an inducible lineage-tracing system based on {beta}5t expression, we explored the early dynamics of the relationships between TEPC and mTEC progenitors and their progeny. Our results identified two potential lineage-biassed TEPC subpopulations, distinguished by Ly6d expression. Additionally, we observed that ageing disproportionately affects Ly6d- compared to Ly6d+ TEPCs, with implications for the rejuvenation of the ageing thymic epithelium. This study provides insights into the developmental pathways of TEC lineages and their maintenance, contributing to strategies for enhancing thymic function in ageing and disease.
Longevity Relevance Analysis
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The study identifies two subpopulations of thymic epithelial progenitor cells (TEPCs) and their differential response to aging, suggesting potential strategies for rejuvenating thymic function. This research is relevant as it explores the mechanisms underlying thymic aging, which is a critical aspect of immune system decline associated with aging.
Rebecca C S Ong, Alexander D Tang
· Aging cell
· Experimental and Regenerative Neurosciences, The University of Western Australia, Perth, Australia.
· pubmed
Repetitive transcranial magnetic stimulation (rTMS) is an attractive tool to promote healthy brain ageing in older adults and treat age-related neurological conditions. Despite its popularity, the neurological processes and plasticity mechanisms altered by rTMS in the aged brain,...
Repetitive transcranial magnetic stimulation (rTMS) is an attractive tool to promote healthy brain ageing in older adults and treat age-related neurological conditions. Despite its popularity, the neurological processes and plasticity mechanisms altered by rTMS in the aged brain, and where these changes occur in the brain are unknown. Furthermore, it is not known why different rTMS protocols induce different changes in the aged brain, or why rTMS is less effective in older adults compared to younger adults. Using spatial transcriptomics, we uncovered that rTMS primarily acts on genes related to synaptic plasticity in both cortical and subcortical circuits in aged mice, but the specific changes were dependent on the brain region and even down to individual cortical layers in the motor and somatosensory cortices. Comparing our results from aged mice to young adult mice revealed that rTMS acts on a larger variety of neural plasticity mechanisms in the young adult brain, and that rTMS was less effective at altering gene expression related to neural plasticity in the aged brain, but this varied between brain regions and the protocol of rTMS applied. These findings provide a comprehensive map of the mechanisms altered by rTMS across the aged brain and highlight the need to consider the effect of ageing when optimising rTMS protocols for older populations.
Longevity Relevance Analysis
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The paper claims that repetitive transcranial magnetic stimulation (rTMS) induces different neural plasticity mechanisms in the aged brain compared to younger brains. This research is relevant as it explores the underlying mechanisms of neural plasticity in the context of aging, which could inform strategies for promoting healthy brain aging and addressing age-related neurological conditions.
Dimitris-Foivos Thanos, Orestis A Ntintas, Emmanouil I Athanasiadis ...
· Cellular Senescence
· Molecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
· pubmed
Chromatin, the spatial organizer of genomic DNA, is hierarchically folded into higher-order structures to facilitate DNA compaction, enabling genome surveillance. Understanding the organization and function of the three-dimensional (3D) genome is critical to profile chromatin acc...
Chromatin, the spatial organizer of genomic DNA, is hierarchically folded into higher-order structures to facilitate DNA compaction, enabling genome surveillance. Understanding the organization and function of the three-dimensional (3D) genome is critical to profile chromatin accessibility and functional interactions that govern gene regulation across multiple biological processes, including aging and one of its hallmarks, cellular senescence. Cellular senescence constitutes a defensive stress response to various intrinsic and extrinsic stimuli, preserving cellular and organismal homeostasis through a generally irreversible cell cycle arrest. In this review article we discuss epigenetic alterations occurring to DNA and chromatin that drive and fuel the onset of this complex phenomenon. As such, we describe major large-scale chromatin events, including the formation of higher-order chromatin structures and the 3D spatial alterations of the genome that occur during senescence. We also discuss global heterochromatin loss, deficiencies in nuclear lamins, the depletion of core histones and their modifications, as well as the epigenetic regulation of the senescence-associated secretory phenotype (SASP), all of which serve key roles in the epigenome of senescent cells. To clearly demonstrate the significance of epigenetic modifications, data from a computational meta-analysis are presented, aiming to further underpin key epigenetic mechanisms occurring in senescent cells. Last, we highlight promising epigenetic modulators implemented in therapeutic strategies for senescent cell detection and elimination, possibly leading to significant clinical advances against various age-related diseases as well as the delay and prevention of the aging onset.
Longevity Relevance Analysis
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The paper discusses the epigenetic alterations in cellular senescence and their implications for aging and age-related diseases. This research is relevant as it addresses the underlying mechanisms of cellular senescence, which is a key contributor to the aging process and potential therapeutic strategies for longevity.
Thi Quynh Trang Nguyen, Kyung A Cho
· Experimental & molecular medicine
· Department of Biochemistry, Chonnam National University Medical School, Hwasun-gun, Republic of Korea.
· pubmed
Here we examine the crucial role of the immune system in aging, with a particular focus on two interconnected processes: immunosenescence and inflammaging, which contribute to age-related decline. Our goal is to provide a thorough overview of the various factors that lead to immu...
Here we examine the crucial role of the immune system in aging, with a particular focus on two interconnected processes: immunosenescence and inflammaging, which contribute to age-related decline. Our goal is to provide a thorough overview of the various factors that lead to immune aging while introducing therapeutic approaches that can partially restore immune function. Additionally, we discuss recent strategies that go beyond localized immune improvement to actively modulate immune balance, influencing systemic aging and extending healthspan. Through this exploration, we propose that regulating the immune system is essential for managing immune aging and may serve as a key mechanism for controlling the overall aging process and promoting healthy longevity.
Longevity Relevance Analysis
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Regulating the immune system can manage immune aging and promote healthy longevity. The paper addresses the root causes of aging by focusing on immunosenescence and inflammaging, which are critical processes in the aging mechanism.
Study of cellular senescence is critical in aging research and anti-senescence therapy drug development. Current methods for the evaluation of the widely accepted cellular senescence marker senescence-associated beta galactosidase (SA-β-gal) activity assay rely on bright-field im...
Study of cellular senescence is critical in aging research and anti-senescence therapy drug development. Current methods for the evaluation of the widely accepted cellular senescence marker senescence-associated beta galactosidase (SA-β-gal) activity assay rely on bright-field imaging, which is non-quantitative and tedious to perform. We have developed an effective and reproducible multiplex high-content analysis system for high-throughput screen and evaluation of senescence modulators. The IC
Longevity Relevance Analysis
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The paper claims to have developed a multiplex high-content analysis system for high-throughput screening of senescence modulators. This research is relevant as it addresses cellular senescence, a key factor in aging and age-related diseases, and proposes a novel method for evaluating potential anti-senescence therapies.
Jiayu Huang, Lu Sun, Yuehan Yin ...
· Cell reports
· Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, Guangdong 518107, China; Department of Urology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, China.
· pubmed
Aging is closely related to the decline of male reproductive endocrine function, which is manifested as insufficient testosterone production. It is well known that stem cell pool stability is crucial for maintaining tissue function. However, the relationship between aging and the...
Aging is closely related to the decline of male reproductive endocrine function, which is manifested as insufficient testosterone production. It is well known that stem cell pool stability is crucial for maintaining tissue function. However, the relationship between aging and the stem Leydig cell (SLC) pool homeostasis remains unclear. Here, we demonstrate that extracellular matrix (ECM) stiffness increases in aging testes, and SLC pool homeostasis is imbalanced. Mechanistically, high ECM stiffness increases calcium influx mediated by Piezo1, leading to mitochondrial dysfunction and excessive reactive oxygen species (ROS). Excessive ROS promotes Gli1 degradation via the ubiquitin-proteasome pathway, ultimately inhibiting the proliferation and differentiation ability of SLCs. Together, these findings reveal the role of ECM stiffness, a biomechanical property in testes, in regulating SLC pool homeostasis and suggest that pretreatment of SLCs with low ECM stiffness in vitro may be an effective strategy for their expansion and for restoring testosterone levels in aging males.
Longevity Relevance Analysis
(4)
High matrix stiffness in aging testes disrupts stem Leydig cell pool homeostasis, leading to decreased testosterone production. This paper addresses a potential root cause of aging-related decline in male reproductive function, making it relevant to longevity research.
Haiyue Tang, Wenjie Ma, Guoyou Zhang ...
· Molecular diversity
· Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area, Ministry of Education, Peptide & Protein Drug Research Center, School of Pharmacy, Ningxia Medical University, Yinchuan, 750004, China.
· pubmed
SIRT6, a pivotal member of the NAD
SIRT6, a pivotal member of the NAD
Longevity Relevance Analysis
(4)
The paper claims to elucidate the mechanistic basis of allostery in SIRT6, which is implicated in metabolic regulation and DNA repair. Understanding SIRT6's role could provide insights into mechanisms of aging and longevity, making it relevant to the field.
Bopp, V., LeeBae, J., Oeckl, P. ...
· neuroscience
· German Center for Neurodegenerative Diseases (DZNE)
· biorxiv
Aging as well as the presence of a-synuclein (a-syn) oligomers in the brain are indisputably linked to Parkinsons disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biologi...
Aging as well as the presence of a-synuclein (a-syn) oligomers in the brain are indisputably linked to Parkinsons disease (PD). A central concept of geroscience is that the biological processes of aging drive the onset of aging-associated diseases. The extent to which the biological processes of aging directly contribute to PD and the inter-relationship with a-syn oligomers for the onset of PD symptoms remains unclear. Using an inducible a-syn oligomer mouse model of PD, we demonstrate that the induction of PD associated a-syn oligomers for the same timespan caused PD associated symptoms only in aged, but not in young mice. Biochemical studies revealed that a-syn oligomer formation precedes motor decline in these aged mice, and age together with a-syn expression determine the motor phenotype. Single-nucleus RNA sequencing (snRNA-seq) identified a PD disease signature that was particularly linked to basal ganglia neurons (BGNs) and was in part shared with an aging transcriptional signature. PD symptoms, as well as the PD Signature, were significantly altered by a short-term pharmacological attenuation of the activity of the small RhoGTPase CDC42 in already aged animals with PD symptoms. Attenuation of activity of CDC42 is known to target the general biological processes of aging. Interestingly, the intervention did not affect the amount of a-syn oligomers in the animals, while still improving phenotypes. Together, the data demonstrates that the biological processes of aging are a major causative driver for the onset of PD in the a-syn model of PD.
Longevity Relevance Analysis
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The paper claims that biological processes of aging are a major causative driver for the onset of Parkinson's Disease in an a-synuclein model. This research is relevant as it explores the intersection of aging mechanisms and neurodegenerative disease, potentially addressing root causes rather than just symptoms.
Tripathi, U., Suda, M., Kulshreshtha, V. ...
· cell biology
· Center for Advanced Gerotherapeutics, Division of Endocrinology and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA
· biorxiv
The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that ar...
The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30-70% of SCs, act by transiently disabling the senescent cell anti-apoptotic pathways (SCAPs), which defend those SCs that are pro-apoptotic and pro-inflammatory from their own senescence-associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro-inflammatory SASP of senescent human preadipocytes, caused them to become senolytic-resistant. Administering senolytics to obese mice selectively decreased abundance of the subset of SCs that is pro-inflammatory. In cell cultures, the 30-70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic-resistant (to Dasatinib or Quercetin, respectively) had increased p16INK4a, p21CIP1, senescence-associated {beta}-galactosidase (SA{beta}gal), {gamma}H2AX, and proliferative arrest similarly to the total SC population (comprising senolytic-sensitive plus -resistant SCs). However, the SASP of senolytic-resistant SCs entailed less pro-inflammatory/ apoptotic factor production, induced less inflammation in non-senescent cells, and was equivalent or richer in growth/ fibrotic factors. Senolytic-resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti-inflammatory immune evasion signal, glycoprotein non-melanoma-B (GPNMB). Transplanting senolytic-resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of pro-apoptotic SASP factors, while pathogen-associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as senosensitizers), senolytic-resistant and senolytic-sensitive SCs appear to be interconvertible.
Longevity Relevance Analysis
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The paper claims that senolytic-resistant senescent cells have a distinct SASP profile that could inform the development of senosensitizers. This research is relevant as it addresses the mechanisms of senescence and potential interventions that could mitigate age-related dysfunction, contributing to the understanding of aging and longevity.
Chandramouli Muralidharan, Enikő Zakar-Polyák, Anita Adami ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, Lund University, Lund, 221 84, Sweden.
· pubmed
Aging is the primary risk factor for most neurodegenerative diseases, yet the cell-type-specific progression of brain aging remains poorly understood. Here, human cell-type-specific transcriptomic aging clocks are developed using high-quality single-nucleus RNA sequencing data fr...
Aging is the primary risk factor for most neurodegenerative diseases, yet the cell-type-specific progression of brain aging remains poorly understood. Here, human cell-type-specific transcriptomic aging clocks are developed using high-quality single-nucleus RNA sequencing data from post mortem human prefrontal cortex tissue of 31 donors aged 18-94 years, encompassing 73,941 high-quality nuclei. Distinct transcriptomic changes are observed across major cell types, including upregulation of inflammatory response genes in microglia from older samples. Aging clocks trained on each major cell type accurately predict chronological age, capture biologically relevant pathways, and remain robust in independent single-nucleus RNA-sequencing datasets, underscoring their broad applicability. Notably, cell-type-specific age acceleration is identified in individuals with Alzheimer's disease and schizophrenia, suggesting altered aging trajectories in these conditions. These findings demonstrate the feasibility of cell-type-specific transcriptomic clocks to measure biological aging in the human brain and highlight potential mechanisms of selective vulnerability in neurodegenerative diseases.
Longevity Relevance Analysis
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The paper develops human cell-type-specific transcriptomic aging clocks that can measure biological aging in the brain. This research is relevant as it addresses the biological mechanisms of aging and their implications for neurodegenerative diseases, contributing to the understanding of aging processes rather than merely treating symptoms.
Masato Horino, Kenji Ikeda, Rei Okazaki ...
· Reactive Oxygen Species
· Department of Molecular Endocrinology and Metabolism, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-ku, 113-8510, Tokyo, Japan.
· pubmed
The induction of beige adipocytes is significantly reduced in aged mice due to the senescence of adipocyte progenitor cells (APCs). Recent studies have revealed the existence of beige adipocyte subtypes, suggesting that APCs comprise a heterogeneous population. Therefore, in this...
The induction of beige adipocytes is significantly reduced in aged mice due to the senescence of adipocyte progenitor cells (APCs). Recent studies have revealed the existence of beige adipocyte subtypes, suggesting that APCs comprise a heterogeneous population. Therefore, in this study, we aimed to elucidate the mechanism through which long-term cold exposure induces the production of beige adipocytes even in aged mice. Single-cell RNA sequencing identified carbonic anhydrase 4 (Car4)-positive APCs. The number of Car4-positive APCs increased with age and cold exposure. Car4 knockdown (KD) mitigated intracellular pH reduction and significantly suppressed beige adipocyte differentiation. Furthermore, Car4 KD cells demonstrated reduced expression of genes in the glutathione pathway and increased susceptibility to reactive oxygen species (ROS), which was alleviated by glutathione supplementation. Our findings suggest that ROS resistance is an adaptation to the cellular aging environment. Our study provides insights into the age-related decline in beige adipocyte induction and identifies Car4 as a potential therapeutic target for enhancing energy expenditure in elderly individuals. This may pave the way for the development of new strategies to combat age-related metabolic diseases and offer hope for improved health and longevity in an aging population.
Longevity Relevance Analysis
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The study claims that Car4-positive adipocyte progenitor cells adapt to aging by enhancing resistance to reactive oxygen species through glutathione metabolism. This research is relevant as it explores mechanisms that could potentially mitigate age-related metabolic decline and improve health in the elderly, addressing root causes of aging rather than merely treating symptoms.
Manmeet Bhalla, Shaunna R Simmons, Alexsandra Lenhard ...
· mSphere
· Department of Microbiology and Immunology, University at Buffalo School of Medicine, , Buffalo, New York, USA.
· pubmed
In response to damage triggered by various stimuli including infections, ATP is released from damaged cells and converted to adenosine in the extracellular space by the ectonucleotidases CD39 and CD73. Extracellular adenosine is an immune modulatory molecule that signals via four...
In response to damage triggered by various stimuli including infections, ATP is released from damaged cells and converted to adenosine in the extracellular space by the ectonucleotidases CD39 and CD73. Extracellular adenosine is an immune modulatory molecule that signals via four G-protein receptors: A1, A2A, A2B, and A3, which can have opposing downstream effects on immune responses. In this minireview, we follow up on our mSphere of Influence commentary that focused on the A2B receptor (2019) to give a broader view of the role of the extracellular adenosine signaling pathway in host defense against infections. Studies demonstrate that extracellular adenosine serves as a key signaling molecule regulating the balance between effective pathogen clearance and immunopathology during infection. Extracellular adenosine displays dose- and time-dependent roles during infection, with individual adenosine receptors playing specific roles in controlling immune responses. Age-driven changes in this pathway contribute to the increased susceptibility of older hosts to certain infections, although there are several key unanswered questions about the role of the extracellular adenosine pathway in immunosenescence. Clinical and translational findings reveal a role for extracellular adenosine production and signaling in infections in humans, and there have been recent advances, but several ongoing challenges remain in pharmacologically targeting this pathway to reshape host immune responses.
Longevity Relevance Analysis
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The paper discusses the role of extracellular adenosine signaling in regulating immune responses during infections, particularly in the context of aging. This research is relevant as it explores how age-related changes in immune signaling pathways may contribute to increased susceptibility to infections in older individuals, addressing a key aspect of immunosenescence.
Aisin, S. I., Lidskii, B. V., Lidsky, P. V.
· evolutionary biology
· Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Tat Chee Ave, Kowloon, Hong Kong SAR
· biorxiv
The biological feasibility of human rejuvenation remains a subject of intense debate, yet answering this question is critical for guiding research strategies. Should aging research focus on reversing aging in older individuals, or on pausing its progression at earlier ages? We ad...
The biological feasibility of human rejuvenation remains a subject of intense debate, yet answering this question is critical for guiding research strategies. Should aging research focus on reversing aging in older individuals, or on pausing its progression at earlier ages? We address this question with evolutionary biology. Classic evolutionary theories of aging - damage accumulation, antagonistic pleiotropy, and the disposable soma - consider aging as a detrimental byproduct of evolution. From this perspective, rejuvenation should confer strong fitness advantages and therefore be expected to evolve in species experiencing substantial aging in the wild. Its rarity in nature should thus be interpreted as evidence of its mechanistic implausibility. Yet, rejuvenation does occur in a few species, and, paradoxically, it is typically induced by stress but not used under optimal conditions. Using mathematical modeling of lifespan plasticity in eusocial insects, we show that this pattern cannot be reconciled with classic theories of aging, revealing an internal contradiction between these theories and the observed avoidance of rejuvenation. By contrast, the pathogen control hypothesis - which interprets aging as an adaptive, programmed process -offers a consistent evolutionary framework for understanding and potentially achieving rejuvenation.
Longevity Relevance Analysis
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The paper claims that the avoidance of rejuvenation in species is inconsistent with classic evolutionary theories of aging and suggests a new framework for understanding rejuvenation. This research is relevant as it addresses fundamental questions about the mechanisms of aging and potential strategies for rejuvenation, which are central to longevity research.
Ge, Y., Zhang, F., Liu, Y. ...
· bioinformatics
· Nanyang Technological University
· biorxiv
Extracting coherent, biologically meaningful insights from vast, complex multi-omics data remains challenging. Currently, pathway enrichment analysis serves as a cornerstone for the functional interpretation of such data. However, conventional approaches often suffer from extensi...
Extracting coherent, biologically meaningful insights from vast, complex multi-omics data remains challenging. Currently, pathway enrichment analysis serves as a cornerstone for the functional interpretation of such data. However, conventional approaches often suffer from extensive functional redundancy caused by shared molecular components and overlapping pathway definitions across databases. This redundancy can obscure key biological signals and compromise the interpretability of pathway enrichment results. Here, we present MAPA (Functional Module Identification and Annotation for Pathway Analysis Results Using Large Language Models [LLM]), an open-source computational framework that resolves redundancy and enhances pathway analysis result interpretation. MAPA computes functional similarity between pathways using LLM-based text embeddings, enabling comparison across different databases. It constructs pathway similarity networks and identifies functional modules via community detection algorithms. Crucially, MAPA employs LLMs for automated functional annotation, integrating Retrieval-Augmented Generation (RAG) to generate comprehensive and real-time biological summaries and reduce hallucinations. Benchmarking demonstrated MAPA\'s superior performance: the biotext embedding similarity showed a large effect size (Cliff\'s {delta} = 0.96) compared with the Jaccard index ({delta} = 0.73), and module identification achieved high accuracy (Adjusted Rand Index [ARI] = 0.95) versus existing methods (ARI = 0.23-0.33). Human expert evaluation confirmed that MAPA\'s annotations match expert-quality interpretations. Finally, a multi-omics aging case study illustrates that MAPA uncovers coherent functional modules and generates insights extending beyond conventional pathway analyses. Collectively, MAPA represents a significant advance in redundancy-aware pathway analysis, transforming pathway enrichment results from fragmented lists into biologically coherent narratives. By leveraging the capabilities of LLMs, MAPA offers researchers a robust, scalable tool for deriving deep mechanistic insights from complex and vast multi-omics datasets, marking a new direction for AI-driven bioinformatics.
Longevity Relevance Analysis
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MAPA enhances pathway analysis by resolving redundancy and providing deep biological interpretations of multi-omics data. The paper is relevant as it addresses complex biological insights that could contribute to understanding the mechanisms of aging and potentially inform strategies for lifespan extension.
Daniel L Vera, Patrick T Griffin, David Leigh ...
· The journals of gerontology. Series A, Biological sciences and medical sciences
· VoLo Foundation, Palm Beach, FL 33410 USA.
· pubmed
Biological age refers to a person's overall health in aging, as distinct from their chronological age. Diverse measures of biological age, referred to as "clocks", have been developed in recent years and enable risk assessments, and an estimation of the efficacy of longevity inte...
Biological age refers to a person's overall health in aging, as distinct from their chronological age. Diverse measures of biological age, referred to as "clocks", have been developed in recent years and enable risk assessments, and an estimation of the efficacy of longevity interventions in animals and humans. While most clocks are trained to predict chronological age, clocks have been developed to predict more complex composite biological age outcomes, at least in humans. These composite outcomes can be made up of a combination of phenotypic data, chronological age, and disease or mortality risk. Here, we develop the first such composite biological age measure for mice: the mouse phenotypic age model (Mouse PhenoAge). This outcome is based on frailty measures, complete blood counts, and mortality risk in a longitudinally assessed cohort of male and female C57BL/6 mice. We then develop clocks to predict Mouse PhenoAge, based on multi-omic models using metabolomic and DNA methylation data. Our models accurately predict Mouse PhenoAge, and residuals of the models are associated with remaining lifespan, even for mice of the same chronological age. These methods offer novel ways to accurately predict mortality in laboratory mice thus reducing the need for lengthy and costly survival studies.
Longevity Relevance Analysis
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The paper claims to develop a composite biological age measure for mice that predicts mortality risk based on multi-omic data. This research is relevant as it addresses biological aging mechanisms and offers a novel approach to assess longevity interventions in a model organism, potentially advancing our understanding of aging and lifespan extension.
Homann, J., Korologou-Linden, R., Viallon, V. ...
· neurology
· Institute of Epidemiology and Social Medicine, University of Muenster, Muenster, Germany; Ageing and Epidemiology Unit (AGE), School of Public Health, Imperial
· medrxiv
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. Methods: We leveraged the European Prospective Investigation into C...
Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder with a largely unknown duration and pathophysiology of the pre-diagnostic phase, especially for the common non-monogenic form. Methods: We leveraged the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort with up to 30 years of follow-up to identify incident ALS cases across five European countries. Pre-diagnostic plasma samples from initially healthy participants underwent high-throughput proteomic profiling (7,285 protein markers, SomaScan). Cox proportional hazards models based on 4,567 participants (including 172 incident ALS cases) were used to identify protein biomarkers associated with future ALS diagnosis. Top results were indirectly validated in two independent case-control studies of prevalent ALS (n=417 ALS, 852 controls). Functional annotation included cross-disease comparisons, gene set and tissue enrichment testing, organ-specific proteomic clocks, and the application of large-language models (LLM). Findings: Five proteins (SECTM1, CA3, THAP4, KLHL41, SLC26A7) were identified as significant pre-diagnostic ALS biomarkers (FDR=0.05), detectable approximately two decades before diagnosis. Of these, all except SECTM1 were indirectly validated in independent cohorts of prevalent ALS cases, supporting their clinical significance. Additionally, 22 nominally significant (p<0.05) pre-diagnostic biomarkers were FDR-significant in prevalent ALS with consistent effect directions. Cross-disease comparisons with pre-diagnostic Parkinson and Alzheimer disease suggested a largely specific pre-diagnostic ALS biomarker signature. Gene ontology and tissue enrichment highlighted early involvement of immune, muscle, metabolic, and digestive processes. Furthermore, analyses of proteomic clocks revealed accelerated aging in brain-cognition, immune, and muscle tissues before clinical diagnosis. Druggability and LLM analyses revealed possible therapeutic targets and novel strategies, emphasizing translational relevance. Interpretation: Our study provides first evidence of ultra-early molecular changes in common ALS up to two decades prior to clinical onset, mainly affecting immune, muscle, metabolic, digestive, and cognitive systems. Our study nominates several compelling candidates for risk stratification studies and novel therapeutic targets for early intervention.
Longevity Relevance Analysis
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The study identifies pre-diagnostic biomarkers for ALS that indicate molecular changes up to two decades before clinical onset. This research is relevant as it explores early biological changes associated with a neurodegenerative disease, potentially contributing to understanding aging processes and identifying targets for early intervention.
Matthew A McLoughlin, Sruthi Cheloor Kovilakam, William G Dunn ...
· Nature genetics
· Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
· pubmed
The mechanisms through which mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid malignancies, and their close association with advanced age, remain poorly understood. Here we show that telomere maintenance plays an important role in this phenomenon. Fi...
The mechanisms through which mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid malignancies, and their close association with advanced age, remain poorly understood. Here we show that telomere maintenance plays an important role in this phenomenon. First, by studying 454,098 UK Biobank participants, we find that, unlike most CH subtypes, splicing-factor-mutant CH is more common in those with shorter genetically predicted telomeres, as is CH with mutations in PPM1D and the TERT gene promoter. We go on to show that telomere attrition becomes an instrument for clonal selection in advanced age, with splicing factor mutations 'rescuing' HSCs from critical telomere shortening. Our findings expose the lifelong influence of telomere maintenance on hematopoiesis and identify a potential shared mechanism through which different splicing factor mutations drive leukemogenesis. Understanding the mechanistic basis of these observations can open new therapeutic avenues against splicing-factor-mutant CH and hematological or other cancers.
Longevity Relevance Analysis
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Telomere attrition influences clonal selection in aging hematopoiesis and leukemogenesis through splicing factor mutations. The study addresses the role of telomere maintenance in the aging process and its implications for understanding the mechanisms of age-related diseases, which is central to longevity research.
Cheyenne Rechsteiner, Francesco Morandini, Sei Joong Kim ...
· Nature aging
· Department of Biology, University of Rochester, Rochester, NY, USA.
· pubmed
The comparative biology of aging leverages the remarkable diversity in aging rates and lifespans across species to uncover naturally evolved adaptations that promote longevity, disease resistance and injury resilience. The beauty of comparative biology is that it discovers adapta...
The comparative biology of aging leverages the remarkable diversity in aging rates and lifespans across species to uncover naturally evolved adaptations that promote longevity, disease resistance and injury resilience. The beauty of comparative biology is that it discovers adaptations that evolved outside of the protected laboratory environment, shaped by natural selection under real-world pressures. In this Review, we outline key approaches in comparative biology of aging studies, including the study of public mechanisms, which are shared between species, and private mechanisms, which are species-specific. Additionally, we present insights gained through high-throughput omics technologies-including genomics, transcriptomics, epigenomics, proteomics and metabolomics-and illustrate how these findings advance our understanding of how to ameliorate the hallmarks of aging, enhance cancer resistance and improve regeneration, with a focus on mammals. Finally, we offer practical guidance for designing and interpreting comparative studies aimed at understanding and translating longevity mechanisms.
Longevity Relevance Analysis
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The paper claims that understanding the comparative biology of aging can uncover adaptations that promote longevity and disease resistance. This research is relevant as it addresses the root causes of aging and seeks to identify mechanisms that could lead to lifespan extension and improved health in aging populations.
Pyne, S., Ray, D., Ray, M. S.
· bioinformatics
· Health Analytics Network, LLC
· biorxiv
With a general increase in human lifespan, the need for technological advances to develop strategies for healthy aging has assumed great importance. In the present study, our goal is to predict the progression of selected aging phenotypes in a given healthy individual as one cont...
With a general increase in human lifespan, the need for technological advances to develop strategies for healthy aging has assumed great importance. In the present study, our goal is to predict the progression of selected aging phenotypes in a given healthy individual as one continues aging past 65 years. Therefore, we developed a novel framework called Dynamic Views of Aging with conditional Generative Adversarial Networks (or DyViA-GAN) which is capable of predicting the plausible personalized trajectories of a selected aging phenotype conditioned on the available measurements of the phenotype at a few initial time instances, and additional covariates. Given the prevalence of osteoporosis in the aging population, we selected total hip Bone Mineral Density (BMD) of a healthy individual as the phenotype of interest, and baseline individual Body Mass Index (BMI) as the covariate. We trained DyViA-GAN on a publicly available longitudinal dataset of a large cohort of mostly white women in the United States of age 65 years or above. Thus, it generated, for each individual, continuous phenotype trajectories, along with a corresponding region of acceptable predictions, for an age range of 66 to 98 years, for eight different combinations both with and without involving the covariate. Our results clearly demonstrate the potential of generative deep learning frameworks in healthspan research.
Longevity Relevance Analysis
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The paper claims to predict personalized trajectories of aging phenotypes using a generative adversarial network. This research is relevant as it addresses the progression of aging phenotypes, specifically focusing on Bone Mineral Density, which is a significant aspect of healthy aging and longevity.
Samrat Chakraborty, Raz Ben-David, Shenhav Shemer
· The FEBS journal
· Faculty of Biology, Technion Institute of Technology, Haifa, Israel.
· pubmed
Skeletal muscle is essential for life as it enables physical movement, maintains posture, is crucial for breathing, and serves as a major site for energy and carbohydrate metabolism. Pathological conditions that reduce skeletal muscle mass and function-such as muscular dystrophie...
Skeletal muscle is essential for life as it enables physical movement, maintains posture, is crucial for breathing, and serves as a major site for energy and carbohydrate metabolism. Pathological conditions that reduce skeletal muscle mass and function-such as muscular dystrophies, motor-neuron diseases, cancer, type-2 diabetes, or aging-have detrimental effects on human health, reducing quality of life and survival. Currently, exercise is the only validated treatment for increasing muscle mass and function, but it is impractical for bedridden patients or the frail elderly. Significant advances in understanding the molecular mechanisms underlying atrophy of slow- or fast-twitch muscle fibers have identified numerous previously unknown key players that may show promise as potential drug targets. Here, we review these recent advances and discuss the potential of these discovered mechanisms as therapeutic targets to combat muscle wasting.
Longevity Relevance Analysis
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The paper discusses emerging therapeutic targets for combating muscle atrophy, particularly in the context of aging and frailty. The focus on molecular mechanisms underlying muscle wasting is relevant to addressing age-related decline in muscle mass and function, which is a significant aspect of longevity research.
Wencong Lyu, Haochen Wang, Zhehao Du ...
· Enalapril
· The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China.
· pubmed
Aging increases the risk of a myriad of chronic diseases, which are expensive and difficult to treat owing to their various risk factors. Repurposing existing medications has accelerated the development of therapies aimed at slowing aging. In this study, using IMR90 cells and age...
Aging increases the risk of a myriad of chronic diseases, which are expensive and difficult to treat owing to their various risk factors. Repurposing existing medications has accelerated the development of therapies aimed at slowing aging. In this study, using IMR90 cells and aged mice, we revealed that enalapril, a drug widely prescribed for hypertension, can improve both cellular senescence and individual health. Mechanistically, phosphorylated Smad1/5/9 act as pivotal mediators of the anti-senescence properties of enalapril. It stimulates downstream genes involved in cell cycle regulation and antioxidative defenses, facilitating cell proliferation and diminishing the production of reactive oxygen species (ROS), thus increasing the antioxidative ability of enalapril. At the organismal level, enalapril has been shown to bolster the physiological performance of various organs; it notably enhances memory capacity and renal function and relieves lipid accumulation. Our work highlights the potential of enalapril to augment antioxidative defenses and combat the effects of aging, thereby indicating its promise as a treatment strategy for aging-associated diseases and its use for healthy aging.
Longevity Relevance Analysis
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Enalapril improves cellular senescence and health in aging through pSmad1/5/9-driven antioxidative mechanisms. The study addresses the root causes of aging by exploring a repurposed medication that may enhance antioxidative defenses and mitigate aging-related phenotypes, which is directly relevant to longevity research.
Hongkun Li, Nuo Xu, Shuaichen Li ...
· Stem cell research & therapy
· Department of Stomatology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, China.
· pubmed
The age-related functional decline of bone marrow mesenchymal stem cells significantly impairs bone regeneration capacity. Exosomes derived from umbilical cord mesenchymal stem cells (UCMSCs) have emerged as promising therapeutic agents in regenerative medicine and anti-aging res...
The age-related functional decline of bone marrow mesenchymal stem cells significantly impairs bone regeneration capacity. Exosomes derived from umbilical cord mesenchymal stem cells (UCMSCs) have emerged as promising therapeutic agents in regenerative medicine and anti-aging research due to their bioactive cargo and low immunogenicity. This study investigated the rejuvenating potential of UCMSCs-derived exosomes (UCMSC-Exos) on senescent jaw bone marrow mesenchymal stem cells (JBMMSCs) and their ability to enhance bone repair in aged rats.
Longevity Relevance Analysis
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Exosomes derived from umbilical cord mesenchymal stem cells can rejuvenate senescent jaw bone marrow mesenchymal stem cells and enhance their osteogenic differentiation. This research addresses the functional decline of stem cells associated with aging, which is a root cause of age-related degeneration and has implications for regenerative medicine in the context of longevity.
Chengcheng Li, Jiaze Tang, Junshuan Cui ...
· Brain
· Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, People's Republic of China.
· pubmed
The relationship between the brain and aging remains unclear. Our objective is to explore the causal connections between brain structure,gene expression, and traits associated with aging. Mendelian randomization(MR) analysis was conducted to explore the associations between brain...
The relationship between the brain and aging remains unclear. Our objective is to explore the causal connections between brain structure,gene expression, and traits associated with aging. Mendelian randomization(MR) analysis was conducted to explore the associations between brain structures and aging-related traits including GrimAge acceleration(GrimAA), PhenoAge acceleration (PhenoAA), HannumAge acceleration(HannumAA), HorvathAge acceleration(HorvathAA), and leukocyte telomere length(LTL). The Linkage Disequilibrium Score Regression(LDSC) method was employed to identify the shared genetic etiology between brain structures and aging. The Summary Data-based Mendelian Randomization(SMR) was utilized to investigate which brain genes have a causal influence on aging. We also examined the expression of the 8 genes derived from the SMR analysis across different cell types in post-mortem human brain specimens. The phenotypes potentially linked to genetics, as indicated by the LDSC outcomes, are as follows:148 phenotypes with GrimAA,150 phenotypes with HannumAA, 160 phenotypes with HorvathAA, 160 phenotypes with PhenoAA,and 110 phenotypes with LTL. Concerning the causal link between brain structures and aging-related traits, 7 brain structures consistently demonstrated a causative effect on GrimAA, while 29 brain structures exerted a causal influence on PhenoAA.Additionally, 7 BIDs revealed a causal relationship with HannumAA. There are 10 and 14 brain structures have a causative effect on HorvathAA and LTL, respectively. SMR revealed that 8 genes(CCDC144B, SHMT1, FAM106A, FAIM, CTD-2303H24.2, EBAG9P1, USP32P2 and OGFOD3) expression in different brain regions affected aging. These genes exhibit different expression patterns in various cells. Our results are in line with the possibility of a causal connection between aging and brain structure.
Longevity Relevance Analysis
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The paper claims that specific brain structures and genes have a causal influence on various measures of biological age acceleration. This research is relevant as it explores the genetic and structural connections between the brain and aging, potentially addressing root causes of aging rather than merely treating age-related symptoms.
Luke Spray, Gavin Richardson, Laura K Booth ...
· Cardiovascular research
· Translational and Clinical Research Institute, Vascular Biology and Medicine Theme, Faculty of Medical Sciences, Newcastle University, Centre for Life, Newcastle Upon Tyne NE1 3BZ, UK.
· pubmed
Most acquired cardiovascular diseases are more common in older people, and the biological mechanisms and manifestations of aging provide insight into cardiovascular pathophysiology. Measuring aging within the cardiovascular system may help to better understand risk profiles for s...
Most acquired cardiovascular diseases are more common in older people, and the biological mechanisms and manifestations of aging provide insight into cardiovascular pathophysiology. Measuring aging within the cardiovascular system may help to better understand risk profiles for specific individuals and direct targeted preventative therapy. In this review, we explore telomere attrition, cellular senescence, epigenetic modifications, and mitochondrial dysfunction as key molecular mechanisms of aging. These phenomena are associated with cardiovascular disease through endothelial dysfunction and systemic inflammation, which are measurable in clinical practice with a variety of clinical, laboratory, and imaging techniques. Finally, we discuss that the next tools for modelling cardiovascular aging must be capable of incorporating a vast amount of diverse data from a given patient, pointing to recent developments in artificial intelligence and machine learning.
Longevity Relevance Analysis
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The paper claims that measuring and modeling cardiovascular aging can enhance understanding of individual risk profiles and direct targeted preventative therapy. This research is relevant as it addresses the biological mechanisms of aging that contribute to cardiovascular diseases, aiming to improve preventative strategies rather than merely treating symptoms.
Otu-Boakye, S., Natarajan, D., Plakkot, B. ...
· neuroscience
· Oklahoma State University, Stillwater, OK, USA
· biorxiv
Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial ...
Dysregulation in lipid metabolism is increasingly recognized as a key contributor to age-related diseases, including neurodegeneration and cerebrovascular dysfunction. While prior studies have largely focused on glial cells, the impact of lipid dysregulation on brain endothelial aging remains poorly understood. In this study, we conducted a secondary analysis of single-cell transcriptomic data from young and aged mouse brains, with a specific focus on endothelial cells (ECs). Our analyses revealed that aging promotes lipid droplet accumulation in brain ECs. These lipid-laden brain ECs exhibit a transcriptomic signature indicative of impaired blood-brain barrier function, increased cellular senescence, and inflammation in aging. Furthermore, lipid accumulation is associated with an altered metabolic phenotype characterized by increased fatty acid oxidation and decreased glycolysis, and impaired mitochondrial electron transport chain activity in the ECs of the aging brain. We have also validated lipid accumulation in aged ECs in vivo. Collectively, our findings indicate that lipid accumulation drives structural, functional, and metabolic impairments in the brain ECs, likely contributing to cerebrovascular aging. Understanding the mechanisms underlying lipid accumulation-induced endothelial dysfunction may offer novel therapeutic strategies for mitigating microvascular dysfunction and cognitive decline in aging.
Longevity Relevance Analysis
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Lipid accumulation in brain endothelial cells contributes to blood-brain barrier dysfunction and metabolic changes associated with aging. This study addresses the underlying mechanisms of endothelial dysfunction in the aging brain, which is crucial for understanding and potentially mitigating age-related cognitive decline and cerebrovascular issues.
Grahek, I., Leng, X., Fengler, A. ...
· animal behavior and cognition
· University of California, Berkeley
· biorxiv
Older adulthood is associated with declines across a wide range of cognitive functions, limiting the ability to perform tasks necessary for independent living. Changes in cognitive flexibility are a promising candidate mechanism underlying age-related changes in cognition, but th...
Older adulthood is associated with declines across a wide range of cognitive functions, limiting the ability to perform tasks necessary for independent living. Changes in cognitive flexibility are a promising candidate mechanism underlying age-related changes in cognition, but the causes of inflexibility in older adulthood remain elusive. Here we focus on a core feature of flexible cognition: the ability to rapidly transition between different cognitive states when required to do so by changes in the environment or our goals (e.g., moving between states of low vs. high attentional focus). We put forward a dynamical systems model proposing that aging-related cognitive inflexibility arises in part from slowing of transitions between distinct configurations of cognitive control, even when the task is held constant. To test this model, we had participants across the lifespan perform a cognitive task under different performance goals, which induced different control configurations. Using computational modeling, we were able to measure dynamic changes in control configurations to meet different performance goals. This allowed us to simultaneously test three potential sources of age-related decreases in cognitive flexibility: 1) diminished control capacity in environments that require more switching; 2) diminished range of control adjustments; and 3) slower transitions between control states. Of these, we found that age was only associated with transition speed. When given sufficient time to maintain a given goal, older adults were able to adjust control to a similar extent as younger adults; however, when goals changed more frequently, they were more likely to undershoot their target control configuration for that goal, consistent with predictions from our model for longer transition times. Our findings demonstrate that cognitive dynamics, rather than the overall reductions in cognitive ability, are critical for understanding the mechanisms through which cognitive inflexibility arises in older adulthood.
Longevity Relevance Analysis
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The paper claims that slower transitions between cognitive control states contribute to cognitive inflexibility in older adults. This research is relevant as it addresses mechanisms underlying cognitive decline in aging, which is a critical aspect of understanding and potentially mitigating age-related cognitive deterioration.
Liao, G. Y., Klug, J., Dai, S. ...
· pharmacology and toxicology
· University of Washington
· biorxiv
The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lif...
The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were identified by velocity-based K-means clustering (silhouette > 0.5). A subset was monitored for post-treatment survival using Kaplan-Meier analysis. Olfactory preference was preserved by all drugs (d = -1.82 to -1.28, P < 0.01), with strongest effects in rapamycin-treated individuals. Rapamycin-treated males matched or exceeded juvenile locomotor activity; phenylbutyrate reduced male activity (d = 1.49, P < 0.05) and acarbose increased walking-to-running ratios (d = -0.75, P < 0.05). Rapamycin increased central exploration and freezing (d = -1.55, P < 0.0001), while acarbose and phenylbutyrate increased peripheral freezing (d = -0.76, P < 0.05). Rapamycin and phenylbutyrate extended maximum running time (d = -2.30 to -1.32, P < 0.0001), with sex-specific jumping gains in rapamycin-treated females and acarbose-treated males. Post-treatment lifespan was prolonged by rapamycin (HR = 0.42, P < 0.001) and reduced by acarbose in females (HR = 2.92 to 3.03, P < 0.05). Intermittent rapamycin preserved survival, cognition, and locomotion, while acarbose and phenylbutyrate produced selective benefits, supporting A. domesticus as a scalable model for geroprotective drug discovery.
Longevity Relevance Analysis
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Intermittent dosing of rapamycin, acarbose, and phenylbutyrate can extend lifespan and enhance healthy aging in house crickets. The study investigates geroprotective drugs and their effects on lifespan and age-related functional decline, addressing the root causes of aging rather than merely treating symptoms.
Emma A Rodrigues, Abdoul Jalil Djiberou Mahamadou, Sylvain Moreno
· Life Style
· School of Interactive Arts and Technology, Simon Fraser University, Surrey, BC, Canada.
· pubmed
Cognitive aging is a complex process influenced by diverse life experiences and environmental factors. However, some traditional studies have oversimplified this process by assuming that cognitive aging trajectories follow a uniform process and that all individuals will experienc...
Cognitive aging is a complex process influenced by diverse life experiences and environmental factors. However, some traditional studies have oversimplified this process by assuming that cognitive aging trajectories follow a uniform process and that all individuals will experience similar declines. This framework minimizes the impact of external factors, neglecting the diversity observed in the aging population. In fact, research has shown significant inter- and intraindividual variability in cognitive trajectories, with some individuals maintaining stable or even improving cognitive function, while others experience rapid decline. To address this gap, emerging research proposes promising alternatives to the homogenous modelling approaches used, focusing on the identification of latent classes of cognitive trajectories. In this work, we build on this by examining the complex interaction of heterogeneous cognitive trajectories with external factors during the aging process, using episodic memory as a measure of cognitive function. We use longitudinal data from 1746 individuals aged 60 and older, assessed at three times over eight years. Our findings revealed three distinct cognitive trajectories - low cognitive performance with early decline , unmodulated cognitive change and high cognitive performance with late decline - each uniquely influenced by specific lifestyle factors. These findings challenge the current theoretical model of cognitive aging by identifying that factors such as concentration activities and social engagement significantly influence the trajectories of low cognitive performance with early decline and high cognitive performance with late decline, whereas the trajectory of unmodulated cognitive change is largely unaffected by environmental influences. Overall, our results highlight the critical role of individual environmental susceptibility in shaping cognitive trajectories. This research provides key insights into the heterogeneity of cognitive aging and underscores the need for a research paradigm shift in understanding cognitive trajectories' heterogeneity. While further research is required to determine how these findings translate into practice, tailoring interventions to these newly identified cognitive trajectories, we can significantly improve individual and public health outcomes through more precise and effective social prescribing interventions.
Longevity Relevance Analysis
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The paper identifies distinct cognitive trajectories in older adults influenced by lifestyle factors. This research is relevant as it explores the heterogeneity of cognitive aging and suggests that lifestyle interventions could potentially improve cognitive outcomes, addressing root causes of cognitive decline rather than merely treating symptoms.
Chen Liang, Yi Yi, Jia Li ...
· Stem cell research & therapy
· Department of Plastic and Cosmetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, Hubei Province, China.
· pubmed
Skin ageing is a multifactorial process influenced by both intrinsic (genetic and metabolic) and extrinsic (environmental) factors, leading to noticeable changes such as wrinkles, loss of elasticity, and pigmentation disorders. Recent advancements in regenerative medicine have hi...
Skin ageing is a multifactorial process influenced by both intrinsic (genetic and metabolic) and extrinsic (environmental) factors, leading to noticeable changes such as wrinkles, loss of elasticity, and pigmentation disorders. Recent advancements in regenerative medicine have highlighted the potential of exosomes, small extracellular vesicles, in mediating cellular communication and promoting rejuvenation processes in skin tissues. Exosomes are secreted by various cell types and are rich in bioactive molecules such as proteins, lipids, and nucleic acids, which are crucial for modulating physiological responses. Exosomes derived from mesenchymal stem cells (MSCs), adipose-derived stem cells (ADSCs), and other sources have shown promising results in enhancing skin cell proliferation and collagen synthesis and reducing oxidative stress, thereby mitigating both intrinsic and extrinsic skin ageing. Therefore, this review explores the mechanisms through which exosomes exert their effects, including the modulation of signalling pathways involved in cell growth, anti-inflammatory responses, and matrix remodelling. We also explore innovative delivery systems for exosome-based therapies, such as microneedling and hydrogels, which enhance the penetration and efficacy of these vesicles in skin applications. However, despite their potential, the clinical application of exosome-based therapies faces challenges such as scalability of production, standardization of purification methods, and understanding of long-term effects. This comprehensive investigation emphasised the potential of exosomes in the fields of dermatology and regenerative medicine in combating skin ageing.
Longevity Relevance Analysis
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Exosomes derived from various stem cells can enhance skin cell proliferation and reduce oxidative stress, potentially mitigating skin aging. The paper addresses mechanisms that could contribute to combating the root causes of skin aging, aligning with longevity research.