Agus Surachman, Meera N Harhay, Rose Ann DiMaria-Ghalili ...
· GeroScience
· Department of Epidemiology and Biostatistics, Dornsife School of Public Health, Drexel University, 3215 Market St, Rm 552, Philadelphia, PA, 19104, USA. [email protected].
· pubmed
Epigenetic aging measures are novel molecular indicators of biological aging that predict age-related chronic disease. We examined whether several established indices of epigenetic aging mediated the association between life course socioeconomic status (SES) and decrements in kid...
Epigenetic aging measures are novel molecular indicators of biological aging that predict age-related chronic disease. We examined whether several established indices of epigenetic aging mediated the association between life course socioeconomic status (SES) and decrements in kidney function across a decade. Biomarker data were from 252 non-Hispanic (NH) Black and white participants who had consented to genetic analyses in Wave 2 (2004-2009) and 3 (2014-2021) of the Midlife in the United States study (MIDUS). Life course SES included parental education, a proxy of early life SES, and a composite score of adult SES based on the highest education level, household income to poverty line ratio, health insurance coverage, perception of the availability of money to meet needs, and difficulty level paying monthly bills. We included five measures of epigenetic age accelerations (EAA), based on the residuals after each epigenetic clock was regressed on chronological age (Horvath, Horvath blood and skin, Hannum, PhenoAge, and GrimAge) and one measure of the pace of aging (DunedinPACE) obtained during MIDUS 2. Kidney function was based on serum creatinine-based estimated glomerular filtration rate (eGFR), calculated using the CKD-EPI formula (without race adjustment). We calculated absolute decrements in eGFR across 11 years between MIDUS waves 2 and 3. Analyses were adjusted for age, sex, and health-related covariates (currently smoking, obese, hypertension, and insulin resistance). Lower adult SES and accelerated epigenetic aging, especially accelerated GrimAge and faster DunedinPACE pace of aging, mediated the association between lower parental education and larger decrements in eGFR. Accelerated epigenetic aging is associated with larger decrements in kidney function across a decade and may be one of the critical explanatory pathways for the higher burden of chronic kidney disease (CKD) among lower SES individuals.
Longevity Relevance Analysis
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Lower adult socioeconomic status and accelerated epigenetic aging mediate the association between lower parental education and larger decrements in kidney function over a decade. The study addresses the role of epigenetic aging as a potential mechanism linking socioeconomic factors to biological aging and chronic disease, which is pertinent to understanding the root causes of aging.
Ping Wu, Lieselot Vandemeulebroucke, Kevin Rey A Guiritan ...
· The journals of gerontology. Series A, Biological sciences and medical sciences
· Laboratory of Aging Physiology and Molecular Evolution, Department of Biology, Ghent University, 9000 Ghent, Belgium.
· pubmed
Axenic dietary restriction (ADR) represents a powerful and unique DR regimen for C. elegans as it robustly extends lifespan independently of well-known key genes associated with DR, such as those of insulin/IGF-1 signaling, skn-1, and pha-4. Here, we analyze C. elegans survival i...
Axenic dietary restriction (ADR) represents a powerful and unique DR regimen for C. elegans as it robustly extends lifespan independently of well-known key genes associated with DR, such as those of insulin/IGF-1 signaling, skn-1, and pha-4. Here, we analyze C. elegans survival in a dilution series of axenic medium to explore the dependency of lifespan extension on nutrient availability. We find a non-linear relationship between lifespan and axenic nutrient levels with a four-fold axenic dilution yielding peak longevity. Notably, lifespan extension at specific dilutions permits maintenance of reproductive potential and survivability after bacterial reintroduction, indicating a partial reliance on adult reproductive diapause mechanisms. Genetic analyses found the involvement of AMPK/aak-2, sir-2.1, and cbp-1 in mediating lifespan extension across the axenic dilution spectrum, the essential role of daf-16 and hlh-30 under severe nutrient scarcity, and the specific contribution of bli-4 to standard ADR longevity. These findings elucidate that C. elegans lifespan extension under different levels of nutrient restriction is governed by overlapping yet distinct genetic pathways.
Longevity Relevance Analysis
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The paper claims that lifespan extension in C. elegans is influenced by a non-linear relationship with nutrient availability and involves distinct genetic pathways. This research is relevant as it explores mechanisms of lifespan extension and survival responses, contributing to our understanding of aging processes.
Xieyang Xu, Yan Pang, Xianqun Fan
· Oxidative Stress
· Department of Ophthalmology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
· pubmed
Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and anti...
Mitochondria are the energy production centers in cells and have unique genetic information. Due to the irreplaceable function of mitochondria, mitochondrial dysfunction often leads to pathological changes. Mitochondrial dysfunction induces an imbalance between oxidation and antioxidation, mitochondrial DNA (mtDNA) damage, mitochondrial dynamics dysregulation, and changes in mitophagy. It results in oxidative stress due to excessive reactive oxygen species (ROS) generation, which contributes to cell damage and death. Mitochondrial dysfunction can also trigger inflammation through the activation of damage-associated molecular patterns (DAMPs), inflammasomes and inflammatory cells. Besides, mitochondrial alterations in the functional regulation, energy metabolism and genetic stability accompany the aging process, and there has been a lot of evidence suggesting that oxidative stress and inflammation, both of which are associated with mitochondrial dysfunction, are predisposing factors of aging. Therefore, this review hypothesizes that mitochondria serve as central hubs regulating oxidative stress, inflammation, and aging, and their dysfunction contributes to various diseases, including cancers, cardiovascular diseases, neurodegenerative disorders, metabolic diseases, sepsis, ocular pathologies, liver diseases, and autoimmune conditions. Moreover, we outline therapies aimed at various mitochondrial dysfunctions, highlighting their performance in animal models and human trials. Additionally, we focus on the limitations of mitochondrial therapy in clinical applications, and discuss potential future research directions for mitochondrial therapy.
Longevity Relevance Analysis
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Mitochondria play a central role in regulating oxidative stress, inflammation, and aging, suggesting that targeting mitochondrial dysfunction could address root causes of aging. The paper discusses mechanisms of aging and potential therapeutic advances, making it relevant to longevity research.
Na Zhang, Yan You, Yanhua Zhao ...
· Biology of reproduction
· Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing 100191, P. R. China.
· pubmed
The advanced maternal age is strongly correlated with a notable decline in oocyte quality, yet definitive and effective strategies to enhance it remain incompletely identified. In this study, we reported that near-infrared light, administered in vitro, efficaciously improves the ...
The advanced maternal age is strongly correlated with a notable decline in oocyte quality, yet definitive and effective strategies to enhance it remain incompletely identified. In this study, we reported that near-infrared light, administered in vitro, efficaciously improves the quality of post-ovulatory aging (POA) and reproductive aged oocytes by recovering mitochondrial activity. Near-infrared light has the capacity to ameliorate abnormalities in mitochondrial membrane potential, optimize mitochondrial distribution, augment ATP synthesis, and modulate the expression of mitochondrial-related genes. It can consequently enhance the quality of oocytes by reducing the reactive oxygen species (ROS) level, improving the abnormal distribution of spindles and maintaining the fertilization ability. Moreover, transcriptome analysis also shows that the beneficial effect of near-infrared light on POA and reproductive aged oocytes is mediated by restoration of mitochondrial function. Collectively, our data reveal that the near-infrared light treatment, especially of 810 nm or 950 nm with a cumulative dosage of 1.5 J*cm-2, is a feasible approach to protect oocytes from POA and reproductive aged deterioration, contributing to the improvement of reproductive outcomes of aged women and assisted reproductive technology.
Longevity Relevance Analysis
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Near-infrared light treatment improves the quality of post-ovulatory aging and reproductive aged oocytes by enhancing mitochondrial function. This research addresses a fundamental aspect of reproductive aging, which is directly related to the aging process and its effects on fertility, making it relevant to longevity studies.
Haoxian Zhou, Shu Wu, Bin Li ...
· Protein & cell
· Department of Cardiology, Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, China.
· pubmed
Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quad...
Loss of protein homeostasis is a hallmark of cellular senescence, and ribosome pausing plays a crucial role in the collapse of proteostasis. However, our understanding of ribosome pausing in senescent cells remains limited. In this study, we utilized ribosome profiling and G-quadruplex RNA immunoprecipitation sequencing techniques to explore the impact of RNA G-quadruplex (rG4) on the translation efficiency in senescent cells. Our results revealed a reduction in the translation efficiency of rG4-rich genes in senescent cells and demonstrated rG4 structures within coding sequence (CDS) can impede translation both in vivo and in vitro. Moreover, we observed a significant increase in the abundance of rG4 structures in senescent cells, and the stabilization of the rG4 structures further exacerbated cellular senescence. Mechanistically, the RNA helicase DHX9 functions as a key regulator of rG4 abundance, and its reduced expression in senescent cells contributing to increased ribosome pausing. Additionally, we also observed an increased abundance of rG4, an imbalance in protein homeostasis, and reduced DHX9 expression in aged mice. In summary, our findings reveal a novel biological role for rG4 and DHX9 in the regulation of translation and proteostasis, which may have implications for delaying cellular senescence and the aging process.
Longevity Relevance Analysis
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The paper claims that RNA G-quadruplex structures exacerbate cellular senescence by mediating ribosome pausing. This research is relevant as it explores mechanisms that contribute to cellular senescence, which is a key aspect of the aging process and may provide insights into potential interventions for longevity.
Wallis, R., Hughes, B. K., Moore, M. ...
· cancer biology
· Blizard Institute, Queen Mary University of London
· biorxiv
Background Senescence identification is rendered challenging due to a lack of universally available biomarkers. This represents a bottleneck in efforts to develop pro-senescence therapeutics - agents designed to induce the arrest of cellular proliferation associated with a senesc...
Background Senescence identification is rendered challenging due to a lack of universally available biomarkers. This represents a bottleneck in efforts to develop pro-senescence therapeutics - agents designed to induce the arrest of cellular proliferation associated with a senescence response in cancer cells for therapeutic gain. This is particularly true in contexts such as basal-like breast cancer (BLBC), which often express high levels of widely reported senescence hallmarks, which has led to the designation of these subtypes as senescence marker positive (Sen-Mark+). Unfortunately, these are often cancers with the most limited treatment options, where novel pro-senescence compounds would be of potential clinical utility. Results To address these challenges, we have developed SAMP-Score, a machine learning classification tool for identifying senescence induction in Sen-Mark+ cancers. This technique builds upon our previous observation that senescent cells develop distinct senescence-associated morphological profiles (SAMPs), which can be assessed readily in traditionally challenging contexts for senescence identification, including high-throughput screens. Conclusions Through application of SAMP-Score, we have identified QM5928, a novel pro-senescence compound, that is able to induce senescence in a variety of Sen-Mark+ cancers and has potential utility as a tool molecule to explore the mechanisms and pathways through which senescence induction occurs in these cells.
Longevity Relevance Analysis
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The paper claims that the SAMP-Score can identify pro-senescence compounds in cancer cells. This research is relevant as it addresses the challenge of senescence in cancer treatment, potentially contributing to understanding and targeting the aging process at the cellular level.
Shuying Chen, Qian Chen, Xinru You ...
· Nature aging
· Center for Nanomedicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
· pubmed
Aging is characterized by a gradual decline of cellular and physiological functions over time and an increased risk of different diseases. RNA therapeutics constitute an emerging approach to target the molecular mechanisms of aging and age-related diseases via rational design and...
Aging is characterized by a gradual decline of cellular and physiological functions over time and an increased risk of different diseases. RNA therapeutics constitute an emerging approach to target the molecular mechanisms of aging and age-related diseases via rational design and have several advantages over traditional drug therapies, including high specificity, low toxicity and the potential for rapid development and production. Here, we discuss the latest developments in RNA therapeutics designed to promote healthy aging, including RNA activation, messenger RNA therapy, RNA interference, antisense oligonucleotides, aptamers and CRISPR-Cas-mediated RNA editing. We also review the latest preclinical and clinical studies of RNA technology for treating age-related diseases, including neurodegenerative, cardiovascular and musculoskeletal diseases. Finally, we discuss the challenges of RNA technology aimed at supporting healthy aging. We anticipate that the fusion of RNA therapeutics and aging biology will have an important effect on the development of new medicines and maximization of their efficacy.
Longevity Relevance Analysis
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RNA therapeutics can target the molecular mechanisms of aging to promote healthy aging. The paper discusses innovative approaches to address the root causes of aging and age-related diseases, aligning with longevity research goals.
Zhen Yu, Ruiye Chen, Peng Gui ...
· NPJ digital medicine
· The AIM for Health Lab, Monash University, Melbourne, VIC, Australia.
· pubmed
Retinal age has emerged as a promising biomarker of aging, offering a non-invasive and accessible assessment tool. We developed a deep learning model to estimate retinal age with enhanced accuracy, leveraging retinal images from diverse populations. Our approach integrates self-s...
Retinal age has emerged as a promising biomarker of aging, offering a non-invasive and accessible assessment tool. We developed a deep learning model to estimate retinal age with enhanced accuracy, leveraging retinal images from diverse populations. Our approach integrates self-supervised learning to capture chronological information from both snapshot and sequential images, alongside a progressive label distribution learning module to model biological aging variability. Trained and validated on healthy cohorts (34,433 participants from the UK Biobank and three Chinese cohorts), the model achieved a mean absolute error of 2.79 years, surpassing previous methods. When applied to broader populations, analysis of the retinal age gap-the difference between retina-predicted and chronological age-revealed associations with increased risks of all-cause mortality and multiple age-related diseases. These findings highlight the potential of retinal age as a reliable biomarker for predicting survival and aging outcomes, supporting targeted risk management and precision health interventions.
Longevity Relevance Analysis
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The paper claims that retinal age can serve as a reliable biomarker for predicting survival and aging outcomes. This research is relevant as it addresses the assessment of biological aging through a non-invasive method, which could contribute to understanding and potentially mitigating the root causes of aging and age-related diseases.
Sergiy Libert, Alex Chekholko, Cynthia Kenyon
· Aging
· Calico Life Sciences, South San Francisco, United States.
· pubmed
Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individual's age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength, and stimulus-reac...
Why people age at different rates is a fundamental, unsolved problem in biology. We created a model that predicts an individual's age from physiological traits that change with age in the large UK Biobank dataset, such as blood pressure, lung function, strength, and stimulus-reaction time. The model predicted a person's age with best accuracy when it heavily weighted traits that together query multiple organ systems, arguing that most or all physiological systems (lung, heart, brain, etc.) contribute to the global phenotype of chronological age. Differences between calculated 'biological' age and chronological age (∆Age) appear to reflect an individual's relative youthfulness, as people predicted to be young for their age had a lower subsequent mortality rate and a higher parental age at death, even though no mortality data were used to calculate ∆Age. Remarkably, the effect of each year of physiological ∆Age on Gompertz mortality risk was equivalent to that of one chronological year. A genome-wide association study (GWAS) of ∆Age and analysis of environmental factors associated with ∆Age identified known as well as new factors that may influence human aging, including genes involved in synapse biology and a tendency to play computer games. We identify a small number of readily measured physiological traits that together assess a person's biological age and may be used clinically to evaluate therapeutics designed to slow aging and extend healthy life.
Longevity Relevance Analysis
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The paper claims that a mathematical model can predict biological age from physiological traits, which correlates with mortality risk and identifies factors influencing aging. This research is relevant as it addresses the underlying mechanisms of aging and proposes a method to evaluate biological age, potentially leading to interventions that could slow aging and improve healthspan.
Balun Li, Yanheng Ding, Miao Han ...
· Aging
· College of Veterinary Medicine, Shaanxi Centre of Stem Cells Engineering & Technology, Northwest A&F University, Yangling, China.
· pubmed
Dogs serve as ideal research subjects for aging studies. In this study, 9 aging-related cell populations are identified through single-cell RNA sequencing of dogs of different ages. Additionally, 9 CD8+ T cell senescence-specific markers conserved across species are identified. F...
Dogs serve as ideal research subjects for aging studies. In this study, 9 aging-related cell populations are identified through single-cell RNA sequencing of dogs of different ages. Additionally, 9 CD8+ T cell senescence-specific markers conserved across species are identified. Furthermore, multi-omics technology is employed to characterize 17 transcriptional and protein markers, along with 5 metabolic markers, associated with stem cell aging. Penitrem A and UDP-N-acetylglucosamine are further validated as two consistent metabolic markers of both individual and cellular senescence. A customized metabolic assessment system and blood-based assessment framework specifically for aging dogs are developed. Notably, it is demonstrated that mesenchymal stem cells, particularly those overexpressing NMNAT1, can delay or reverse aging in dogs. This study sheds light on the mysteries of aging from multiple perspectives and provides a broad target for future research efforts aimed at uncovering the complexity of this fundamental biological process.
Longevity Relevance Analysis
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The study identifies aging-related markers and demonstrates that mesenchymal stem cells can delay or reverse aging in dogs. This research is relevant as it explores the biological mechanisms of aging and potential interventions, contributing to the understanding of longevity and age-related processes.
Cassandra J McGill, Amy Christensen, Wenjie Qian ...
· Communications medicine
· Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
· pubmed
The apolipoprotein ε4 allele (APOE4) is associated with decreased longevity and increased vulnerability to age-related declines and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development of...
The apolipoprotein ε4 allele (APOE4) is associated with decreased longevity and increased vulnerability to age-related declines and disorders across multiple systems. Interventions that promote healthspan and lifespan represent a promising strategy to attenuate the development of APOE4-associated aging phenotypes. Here, we studied the ability of the longevity-promoting intervention 17α-estradiol (17αE2) to protect against impairments in APOE4 versus the predominant APOE3 genotype using early middle-aged mice with knock-in of human APOE alleles.
Longevity Relevance Analysis
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The paper claims that 17α-estradiol can protect against aging-related impairments associated with the APOE4 genotype in middle-aged mice. This research is relevant as it explores a potential intervention that targets the underlying mechanisms of aging and longevity, specifically in the context of a genetic risk factor for age-related decline.
Gwladys Revêchon, Anna Witasp, Nikenza Viceconte ...
· Nature aging
· Department of Medicine, Huddinge, Karolinska Institutet, Huddinge, Sweden. [email protected].
· pubmed
Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the prote...
Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the protein responsible for the premature aging disease Hutchinson-Gilford progeria syndrome, steadily recurring in vascular smooth muscle cells of patients with CKD. Notably, the most common progeria-causing mutation, LMNA c.1824C>T, was identified as a somatic mutation in CKD arteries. Clusters of proliferative progerin-expressing cells in CKD arteries and in vivo lineage-tracing in mice revealed clonal expansion capacity of mutant cells. Mosaic progerin expression contributed to genomic damage, endoplasmic reticulum stress and senescence in CKD arteries and resulted in vascular aging phenotypes in vivo. These findings suggest that certain somatic mutations may be clonally expanded in the arterial wall, contributing to the disease-related functional decline of the tissue.
Longevity Relevance Analysis
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The paper claims that somatic mutations, particularly progerin expression, contribute to early vascular aging in chronic kidney disease. This research is relevant as it explores the molecular mechanisms underlying aging processes, specifically how somatic mutations may drive age-related vascular decline.
Piero Rigo, Sara Ahmed-de-Prado, Rebecca L Johnston ...
· Hippocampus
· Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
· pubmed
Adult neural stem cells exist on a continuum from deep to shallow quiescence that changes in response to injury or aging; however, the transcription factors controlling these stepwise transitions have not been identified. Single-cell transcriptomic analyses of mice with loss of f...
Adult neural stem cells exist on a continuum from deep to shallow quiescence that changes in response to injury or aging; however, the transcription factors controlling these stepwise transitions have not been identified. Single-cell transcriptomic analyses of mice with loss of function or increased levels of the essential activation factor
Longevity Relevance Analysis
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The paper claims to identify transcription factors that control the activation of hippocampal stem cells in response to aging and injury. This research is relevant as it explores the mechanisms underlying neural stem cell activation, which could contribute to understanding and potentially mitigating age-related decline in cognitive function.
Young Du Choi, Young Un Kim, HyunJoon Gi ...
· BMB reports
· Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212; Program in Biomedical Science & Engineering, Inha University, Incheon 22212; Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon 22212, Korea.
· pubmed
Skin aging is a complex biological process driven by intrinsic and extrinsic factors, leading to a progressive structural and functional decline. The balance between extracellular matrix (ECM) degradation and synthesis is critical for maintaining skin homeostasis, with collagen l...
Skin aging is a complex biological process driven by intrinsic and extrinsic factors, leading to a progressive structural and functional decline. The balance between extracellular matrix (ECM) degradation and synthesis is critical for maintaining skin homeostasis, with collagen loss and reduced cell proliferation contributing to age-related deterioration. Serpin Family A Member 3 (SERPINA3), a serine protease inhibitor, has been implicated in inflammation and tissue remodeling. However, its role in skin aging remains largely unexplored. In this study, we examined the expression and function of SERPINA3 in human skin cells. RNA-seq analysis revealed that SERPINA3 expression is significantly downregulated in aged human dermal fibroblasts and was further diminished under oxidative stress. Functional assays demonstrated that SERPINA3 promotes cell proliferation, accelerates wound healing, and activates key signaling pathways such as ERK and AKT. These findings suggest that SERPINA3 may serve as a protective factor against skin aging by supporting ECM integrity and enhancing cellular regeneration. These results provide novel insights into the molecular functions of SERPINA3 and highlight its potential as a therapeutic target for age-related skin deterioration.
Longevity Relevance Analysis
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SERPINA3 promotes cell proliferation and enhances wound healing in human dermal fibroblasts. The study addresses the role of SERPINA3 in skin aging, focusing on mechanisms that could potentially mitigate age-related decline in skin functionality, thus contributing to the understanding of aging processes.
Fangxi Xu, Yuqi Guo, Scott C Thomas ...
· Dysbiosis
· Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, USA.
· pubmed
Aging involves the accumulation of various forms of molecular and cellular damage over time. Key features of aging, such as mitochondrial dysfunction, dysbiosis, and oxidative stress, are closely linked and largely driven by inflammation. This study examines the role of succinate...
Aging involves the accumulation of various forms of molecular and cellular damage over time. Key features of aging, such as mitochondrial dysfunction, dysbiosis, and oxidative stress, are closely linked and largely driven by inflammation. This study examines the role of succinate, a key metabolite produced and utilized by cells of both host and microbes, and its receptor, succinate receptor 1 (SUCNR1), in age-related oral dysbiosis and inflammation. We examined young and aged wild-type (WT) and SUCNR1 knockout (KO) mice for this analysis. Our findings revealed significant aging-associated alveolar bone loss and succinate elevation in aged WT mice, along with notable changes in the oral microbiome. Conversely, aged KO mice showed reduced bone loss, lower succinate levels, less inflammation, and better-maintained microbial function. These results suggest that SUCNR1 is crucial in influencing aging-related succinate elevation, oral dysbiosis, and inflammation. Analysis of gene families and pathways in the oral microbiome demonstrated distinct aging-related changes between WT and KO mice, with the functional potential being preserved in the KO-aged group. This study underscores the importance of succinate elevation and signaling through SUCNR1 in regulating inflammation, alveolar bone loss, and shifts in the oral microbiome, offering potential targets for therapeutic interventions in age-related oral health issues.
Longevity Relevance Analysis
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Succinate elevation and signaling through SUCNR1 play a crucial role in regulating inflammation, alveolar bone loss, and shifts in the oral microbiome in aged mice. This study addresses mechanisms underlying age-related dysbiosis and inflammation, which are central to the aging process and potential interventions for age-related health issues.
Yi-Wen Liao, Hsi-Hsien Hsieh, Jin-Wei Yeh ...
· Cellular Senescence
· Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
· pubmed
The limited doubling capacity of human cells, known as replicative senescence or cellular senescence, is a major factor in cellular aging. This process is triggered by telomere erosion, which activates a p53-mediated DNA damage response (DDR) that halts cell proliferation. p53, a...
The limited doubling capacity of human cells, known as replicative senescence or cellular senescence, is a major factor in cellular aging. This process is triggered by telomere erosion, which activates a p53-mediated DNA damage response (DDR) that halts cell proliferation. p53, a transcriptional regulator, responds to DNA damage by increasing the expression of the cyclin-dependent kinase inhibitor p21. p21 then arrests cells at specific stages of the cell cycle. Additionally, p53 upregulates serpinB2 (also known as plasminogen activator inhibitor-2, PAI-2), which stabilizes p21 in senescent cells. This study reveals that serpinB2 upregulation activates transglutaminase 2 (TGM2), which selectively deamidates multiple glutamine residues on p21, stabilizing the protein and halting cell proliferation in senescent cells. Moreover, inhibiting TGM2-mediated deamidation accelerates p21 degradation, delaying the onset of senescence. Notably, pharmacological inhibition of TGM2 improves aging phenotypes in an accelerated aging model of chronic kidney disease (CKD). These findings provide crucial insights into the role of TGM2-mediated enzymatic deamidation in senescence and its potential relevance to age-associated conditions.
Longevity Relevance Analysis
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The study claims that transglutaminase 2-mediated deamidation stabilizes p21 during senescence, influencing cellular aging. This research addresses mechanisms underlying cellular senescence, which is a fundamental aspect of aging and has implications for age-related conditions.
Naz Şerifoğlu, Giulia Allavena, Bruno Lopes-Bastos ...
· The EMBO journal
· Institute for Research on Cancer and Aging of Nice (IRCAN), CNRS UMR7284, INSERM U1081, Université Cote d'Azur, 06107, Nice, France.
· pubmed
Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate im...
Telomere shortening occurs in multiple tissues throughout aging. When telomeres become critically short, they trigger DNA-damage responses and p53 stabilization, leading to apoptosis or replicative senescence. In vitro, cells with short telomeres activate the cGAS-STING innate immune pathway resulting in type-I interferon-based inflammation and senescence. However, the consequences of these events for the organism are not yet understood. Here, we show that sting is responsible for premature aging of telomerase-deficient zebrafish. We generated sting-/- tert-/- double-mutant animals and observed a thorough rescue of tert-/- phenotypes. At the cellular level, lack of cGAS-STING in tert mutants resulted in reduced senescence, increased cell proliferation, and decreased inflammation despite similarly short telomeres. Critically, absence of sting function resulted in dampening of the DNA damage response and reduced p53 levels. At the organism level, sting-/- tert-/- zebrafish regained fertility, showed delayed cachexia, and decreased cancer incidence, resulting in increased healthspan and lifespan of telomerase mutant animals.
Longevity Relevance Analysis
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The paper claims that the absence of cGAS-STING in telomerase-deficient zebrafish leads to reduced senescence and increased healthspan and lifespan. This research addresses the mechanisms underlying aging and telomere dysfunction, which are central to understanding and potentially mitigating the aging process.
Lauren Monroe, Samantha Kaonis, Natalie Calahan ...
· Advanced biology
· School of Biomedical Engineering, Colorado State University, 800 Meridian Ave, Fort Collins, CO, 80523, USA.
· pubmed
In eukaryotic cell nuclei, chromatin exhibits a high degree of structural and functional dynamics. Recent findings suggest that chromatin has the ability to reorganize in response to changes within the cellular microenvironment. Such changes include oxidative stress found in hype...
In eukaryotic cell nuclei, chromatin exhibits a high degree of structural and functional dynamics. Recent findings suggest that chromatin has the ability to reorganize in response to changes within the cellular microenvironment. Such changes include oxidative stress found in hyperoxia. While hyperoxia is recognized for causing DNA damage and disrupting cellular functions, the effects it has on chromatin structure and the implications thereof remain poorly understood. In this work, an imaging-based technique is developed to visualize and characterize nanoscale chromatin remodeling under hyperoxia in mesenchymal stromal cells, created via hydrogen peroxide treatment. High spatiotemporal variability of remodeling in different chromatin domains is found. Chromatin remodeling is hindered by the GSK126-mediated inhibition of methyltransferase EZH2, which regulates the chromatin compaction. Independent assays such as ATAC seq further revealed that chromatin is compacted by hyperoxia, which is mitigated by GSK126 pretreatment. Epigenetic modifications and DNA damage under hyperoxia is investigated, which is also found to be affected by the pretreatment of GSK126. The techniques and discoveries provide mechanistic insights into chromatin remodeling, potentially paving the way for novel therapeutic strategies to combat genotoxic oxidative stress-commonly associated with degenerative diseases and aging-and to enhance cell-based therapies in regenerative medicine.
Longevity Relevance Analysis
(4)
The paper claims that hyperoxia induces chromatin remodeling in mesenchymal stromal cells, which can be mitigated by GSK126 treatment. The research explores mechanisms related to oxidative stress and chromatin structure, which are pertinent to understanding cellular aging and potential therapeutic strategies for age-related diseases.
M N Núñez-Lisboa, A H Dewolf
· npj aging
· Laboratory of biomechanics and Physiology of Locomotion, Institute of NeuroScience, Université catholique de Louvain, Louvain-la-Neuve, Belgium.
· pubmed
Exercise induces neural and muscular adaptations, improving muscle mass and function in older adults. We investigated its impact on gait neuromuscular control in young and older adults, classified as more active (young: n = 15, 5185 ± 1471 MET-min/week; old: n = 14, 6481 ± 4846 M...
Exercise induces neural and muscular adaptations, improving muscle mass and function in older adults. We investigated its impact on gait neuromuscular control in young and older adults, classified as more active (young: n = 15, 5185 ± 1471 MET-min/week; old: n = 14, 6481 ± 4846 MET-min/week) or less active (young: n = 14, 1265 ± 965 MET-min/week; old: n = 14, 1473 ± 859 MET-min/week). Isometric maximal voluntary torques were assessed for proximal (knee) and distal (ankle) extensors, and muscle mechanical properties of these muscles were assessed using Myoton. Gait was analysed using ground reaction forces, motion capture, and electromyography. Less active older adults exhibited shorter steps, higher mechanical cost, and greater collision at heel strike. These differences were linked to altered neuromuscular control, wider activation of lumbar and sacral motor pools, different activation timing, and reduced muscle-tendon stiffness. Our findings highlight that physical activity preserves neuromuscular control, muscle mechanical properties, and gait efficiency, mitigating age-related decline.
Longevity Relevance Analysis
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Physical activity preserves neuromuscular control and gait efficiency in older adults, mitigating age-related decline. The study addresses the impact of exercise on fundamental aspects of aging, specifically how it can counteract declines in neuromuscular function, which is crucial for maintaining mobility and independence in older populations.
Gilbert B Ampomah, Eldon R Hard, Matthew Robert Pratt
· Chembiochem : a European journal of chemical biology
· University of Southern California, Chemistry, UNITED STATES OF AMERICA.
· pubmed
The overall process of protein aggregation from soluble species to amyloid fibrils is toxic to neurons and can propagate along neuronal connections in ways that potentially explain the pathological progression in most neurodegenerative diseases. One of these aggregation-prone pro...
The overall process of protein aggregation from soluble species to amyloid fibrils is toxic to neurons and can propagate along neuronal connections in ways that potentially explain the pathological progression in most neurodegenerative diseases. One of these aggregation-prone proteins is α-synuclein (α-Syn), which forms insoluble protein deposits in Parkinson's disease and other synucleinopathies. The majority of cases of Parkinson's disease occur fairly late in life and even early-onset variants of the disease caused by mutations to α-Syn occur towards the end of the lifespan for prehistoric man. This suggests a lack of evolutionary pressure to prevent protein aggregation in animals with similar or shorter lifespans. However, α-Syn is also found in animals with notably longer lifespans. Here, we tested the aggregation propensity of α-Syn sequences from short- and longer-lived animals at a range of evolutionary distances from humans. We find that in general longer-lived animals display slower α-Syn aggregation kinetics and the formation of smaller and less uniform fibrils. Overall, our data indicate that some evolutionary pressure may have existed for preventing α-Syn aggregation, but that pressure was lost in the more recent branch of shorter-lived animals containing humans.
Longevity Relevance Analysis
(4)
Longer-lived animals exhibit slower α-Syn aggregation kinetics compared to shorter-lived animals. The study explores evolutionary adaptations related to protein aggregation, which may provide insights into mechanisms of longevity and age-related diseases.
Schleh, M., Cambraia, A., Cutler, M. ...
· physiology
· Vanderbilt University
· biorxiv
Aging is a major risk factor for insulin resistance and type 2 diabetes, driven in part by declining pancreatic beta cell function. While calorie restriction (CR) initiated early in life improves metabolic health and preserves beta cell function, its impact when initiated later i...
Aging is a major risk factor for insulin resistance and type 2 diabetes, driven in part by declining pancreatic beta cell function. While calorie restriction (CR) initiated early in life improves metabolic health and preserves beta cell function, its impact when initiated later in life remains unclear. We implemented a two-month, 20% CR intervention in 72-week-old male mice and assessed in vivo glucose homeostasis and beta cell function using meal tolerance tests, single cell RNA-sequencing, and confocal microscopy. We found that old mice exposed to CR have significantly improved glucose tolerance due to higher insulin sensitivity, which drives a two-fold reduction in glucose-stimulated beta cell insulin secretion. At the molecular level, CR enhanced beta cell proteostasis by downregulating ER stress pathways. Remarkably, CR reprogrammed the alpha cell transcriptome to suppress antigen presentation pathways and cytokine signaling pathways, including major histocompatibility complex class I (MHC-I) signaling. These transcriptional changes correlated with profound reduction in the density of adaptive immune cells in aging islets, including a near-complete loss of cytotoxic CD8+ T cells due to weakened intercellular communication between antigen-presenting cells with T and B lymphocytes. Importantly, aging human alpha cells from non-diabetic donors display similar proinflammatory phenotypes, including higher expression of MHC-I antigens that correlates with higher density of Cd8+ cells in aging human pancreases. Together, these findings demonstrate that CR remodels aging alpha and beta cell structure-function to modulate immune cell interactions in aging pancreases to mitigate age-related immune activation and islet inflammation.
Longevity Relevance Analysis
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Calorie restriction remodels aging alpha and beta cell structure-function to mitigate age-related immune activation and islet inflammation. The study addresses the underlying mechanisms of aging and metabolic health, focusing on how calorie restriction can influence cellular processes related to aging and immune response, which are critical for longevity research.
Arjun Jain, Yuuki Hosokawa, Kevin Joseph
· Cellular reprogramming
· Retro Biosciences, San Francisco, California, USA.
· pubmed
Sahu et al. (2024) demonstrate that targeted partial reprogramming with Oct4, Sox2, and Klf4 (OSK) delivered via adeno-associated virus (AAV) to Cdkn2a-positive cells rejuvenates senescent cells while maintaining cellular identity. In a progeroid and naturally aged mouse model, a...
Sahu et al. (2024) demonstrate that targeted partial reprogramming with Oct4, Sox2, and Klf4 (OSK) delivered via adeno-associated virus (AAV) to Cdkn2a-positive cells rejuvenates senescent cells while maintaining cellular identity. In a progeroid and naturally aged mouse model, a single AAV injection improved lifespan, reduced inflammation, restored tissue integrity, and enhanced wound healing. Complementary results in human fibroblasts confirmed Cdkn2a-driven OSK expression attenuated inflammation-associated genes during replicative senescence and treatments inducing DNA damage. These encouraging results highlight its potential as a safer alternative to systemic senolytic therapies for age-associated disorders.
Longevity Relevance Analysis
(5)
Targeted partial reprogramming with OSK rejuvenates senescent cells and improves lifespan in aged models. This research addresses the root causes of aging by demonstrating a method to restore function in aged cells, which is directly relevant to longevity and age-related disorders.
Fullerton, M. O., Phillips, L. C., Redgrave, R. E. ...
· genetics
· Newcastle University
· biorxiv
Abstract Background and Aims The sodium-dependent multivitamin transporter, encoded by SLC5A6, mediates cellular uptake of the vitamins, biotin and pantothenic acid, both of which are essential cofactors for energy metabolism. Here, we report two families with SLC5A6 mutations pr...
Abstract Background and Aims The sodium-dependent multivitamin transporter, encoded by SLC5A6, mediates cellular uptake of the vitamins, biotin and pantothenic acid, both of which are essential cofactors for energy metabolism. Here, we report two families with SLC5A6 mutations presenting with early-onset dilated cardiomyopathy (DCM). To investigate the link between vitamin deficiency and DCM, we generated a novel cardiac-specific Slc5a6 knockout (Slc5a6cKO) mouse model and tested the therapeutic potential of vitamin supplementation. Methods Cardiac function in Slc5a6cKO mice was assessed by cardiac magnetic resonance imaging and ECG measurements. Histological, biochemical, and proteomic analyses were conducted to identify structural and metabolic changes. The impact of dietary biotin and pantothenic acid supplementation on disease progression was evaluated. Results Slc5a6cKO mice developed progressive cardiac dysfunction, manifesting as DCM with cardiac dilation, cardiomyocyte hypertrophy, fibrosis, impaired Coenzyme A synthesis, and metabolic imbalance, culminating in premature death by 26 weeks. Proteomic analysis revealed early mitochondrial metabolic disruption and extracellular matrix protein upregulation at 8 weeks, preceding overt cardiac dysfunction. Strikingly, vitamin supplementation from preconception onwards, prevented the cardiac phenotype, preserving cardiac structure, function, morphology and survival. This parallels the clinical outcome in one patient who received early vitamin treatment, compared to another who required a heart transplant following delayed vitamin treatment. Conclusions This study establishes a direct link between SLC5A6-mediated vitamin transport, mitochondrial function, and cardiac health. It highlights how vitamin deficiency contributes to DCM pathogenesis and supports early vitamin supplementation as a potential therapeutic strategy for metabolic cardiomyopathies.
Longevity Relevance Analysis
(4)
The paper claims that vitamin supplementation can prevent dilated cardiomyopathy in a mouse model with SLC5A6 deficiency. This research is relevant as it explores the metabolic underpinnings of a cardiac condition and suggests a potential intervention that could address root causes related to energy metabolism, which is a significant aspect of aging and longevity.
Masahiro Tamura, Wakana Yamashita, Takahide Hibi ...
· Schizosaccharomyces
· Laboratory of Molecular Microbiology, Department of Basic Medicinal Sciences, Graduate School of Pharmaceutical Sciences, Nagoya University, Chikusa-ku, Nagoya, 464-8601, Japan.
· pubmed
Inhibition of the activity of Pma1, a widely conserved P-type proton exporting ATPase, has been shown to extend the chronological lifespan (CLS) in fission yeast Schizosaccharomyces pombe. To develop a specific inhibitor for Pma1 of S. pombe, we focused on Si01, a candidate inhib...
Inhibition of the activity of Pma1, a widely conserved P-type proton exporting ATPase, has been shown to extend the chronological lifespan (CLS) in fission yeast Schizosaccharomyces pombe. To develop a specific inhibitor for Pma1 of S. pombe, we focused on Si01, a candidate inhibitor of Saccharomyces cerevisiae Pma1. First, we have established a method for synthesis of Si01 and then investigated its Pma1 inhibitory activity and lifespan extension effect in fission yeast. Second, we also synthesized derivatives of Si01 and determined the minimum structure required for inhibition of S. pombe Pma1. Here we showed that the inhibitory activity of Pma1 correlates with the effect of lifespan extension. Si01 reduced the activity of purified Pma1 protein and extended the CLS of not only fission yeast but also budding yeast. These results provide a molecular basis for understanding the mechanism of Pma1 inhibition and the potential for developing molecules that regulate lifespan.
Longevity Relevance Analysis
(4)
The paper claims that the inhibition of Pma1 activity extends the chronological lifespan in fission yeast. This research is relevant as it explores a potential mechanism for lifespan extension, addressing the root causes of aging through the inhibition of a conserved proton exporting ATPase.
Shvedova, M., Thanapaul, R. J. R. S., Wang, Q. ...
· cell biology
· Boston University School of Medicine
· biorxiv
The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence-like response can result in impaired healing outcomes....
The transient upregulation of cellular senescence within wound tissues has been demonstrated to be an important biological process facilitating efficient tissue repair. Dysregulation of this transient wound-induced senescence-like response can result in impaired healing outcomes. Given the established age-related decline in tissue regenerative capacity, we hypothesized that alterations in this senescence response contribute to the delayed healing of cutaneous wounds in aged individuals. Our investigation demonstrated a significant delay in the closure of full-thickness dorsal skin wounds in aged mice compared to their young counterparts. Analysis of the wound microenvironment revealed a transient upregulation of senescence-associated markers (p16, p21, senescence-associated {beta}-galactosidase) and senescence-associated secretory phenotype factors in the wound tissue of young mice, a response that was markedly attenuated in aged mice. Single-cell RNA sequencing analysis of all cells isolated from day 6 wounds identified a distinct population of p16+/p21+/Ki67- senescent fibroblasts in young mice, characterized by a transcriptional signature indicative of pro-healing extracellular matrix production, a finding corroborated in human wound tissue from young donors. Crucially, in aged wounds, we observed a lower quantity of these senescent cells, a deficit compounded by a qualitative, age-dependent shift in their function, moving away from beneficial extracellular matrix remodeling towards a more detrimental pro-inflammatory state, which ultimately can contribute to the delayed wound healing.
Longevity Relevance Analysis
(4)
The paper claims that alterations in the cellular senescence response contribute to delayed wound healing in aged individuals. This research addresses a fundamental aspect of aging by exploring how cellular senescence affects tissue repair, which is crucial for understanding and potentially mitigating age-related decline in regenerative capacity.
Samuel D Anderson, Maria Razzoli, Brian Chen ...
· GeroScience
· Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
· pubmed
A strong association exists between exposure to life stressors and accelerated aging in humans and animal models. However, the molecular mechanisms that underlie the adverse effect of stress on aging remain poorly characterized, and there is a paucity of prognostic predictors of ...
A strong association exists between exposure to life stressors and accelerated aging in humans and animal models. However, the molecular mechanisms that underlie the adverse effect of stress on aging remain poorly characterized, and there is a paucity of prognostic predictors of stress-induced disease outcomes and life expectancy. To address this gap, we developed mathematical models to predict remaining lifespan based on healthspan data across two independent cohorts which were part of a large study (350 + mice) on social stress and aging in mice. We then relate remaining lifespan to changes in DNA methylation, due to its strong association with age as well as environmental factors such as stress exposure. Multivariate multiple regression identified blood glucose as a major trait associated with DNA methylation. An independent neural network analysis also identified blood glucose among the traits most associated with mortality risk. Finally, elastic net regression identified several DNA methylation sites, including Ptp4a3, Lrrc3b, Adgrb1, Mron5, and Gm6549, which represent possible targets at the intersection of glucose, stress and survival. Overall, the main finding of our analysis is that epigenetic biomarkers of mortality risk reveal an association with blood glucose levels, informing on individual life trajectories shaped by the impact of chronic social stress.
Longevity Relevance Analysis
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The paper identifies specific DNA methylation sites associated with mortality risk in mice under chronic social stress, linking these epigenetic changes to blood glucose levels. This research is relevant as it explores the molecular mechanisms of aging and stress, contributing to the understanding of longevity and potential interventions.
Takuji Kawamura, Csaba Kerepesi, Juliet Polok Sarkar ...
· Aging cell
· Research Center for Molecular Exercise Science, Hungarian University of Sports Science, Budapest, Hungary.
· pubmed
Epigenetic drift, which is gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging, and the molecular mechanisms underlying their interactions are poorl...
Epigenetic drift, which is gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging, and the molecular mechanisms underlying their interactions are poorly understood. Here, we investigated the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. Epigenetic clocks, trained on available rat blood-derived reduced representation bisulfite sequencing data, did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we observed organ-specific differences in global mean DNA methylation and mean methylation entropy between LCR and HCR rats, and the direction of these differences was the opposite compared to the age-related changes in the rat blood. Notably, the soleus muscle exhibited the most pronounced differences in promoter methylation due to CRF. We also identified seven genes whose promoter methylation was consistently influenced by CRF in all four organs. Moreover, we found that age acceleration of the soleus muscle was significantly higher compared to the heart and the hippocampus, and significantly lower compared to the large intestine. Finally, we found that the age acceleration was not consistent across organs. Our data suggest that CRF associates with epigenetic aging in an organ-specific and organ-common manner. Our findings provide important insights into the biology of aging and emphasize the need to validate rejuvenation strategies in the context of the organ-specific nature of epigenetic aging.
Longevity Relevance Analysis
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The paper claims that cardiorespiratory fitness (CRF) is associated with organ-specific and common epigenetic aging patterns in aged rats. This research is relevant as it explores the relationship between exercise and epigenetic aging, addressing potential mechanisms that could influence longevity and age-related biological processes.
Zhang, W., Lukacsovich, D., Young, J. ...
· genetic and genomic medicine
· University of Miami
· medrxiv
Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. In this study, we performed a meta-analysis of blood DNAm samples from 475 dementia-free su...
Aging is the strongest risk factor for Alzheimer's disease (AD), yet the role of age-associated DNA methylation (DNAm) changes in blood and their relevance to AD remains poorly understood. In this study, we performed a meta-analysis of blood DNAm samples from 475 dementia-free subjects aged over 65 years across two independent cohorts, the Framingham Heart Study (FHS) at Exam 9 and the Alzheimer's Disease Neuroimaging Initiative (ADNI). After adjusting for age, sex, and immune cell type proportions, and correcting for batch effects and genomic inflation, we identified 3758 CpGs and 556 differentially methylated regions (DMRs) consistently associated with aging in both cohorts at a 5% false discovery rate. Our pathway enrichment analyses highlighted immune response, metabolic regulation, and synaptic plasticity, all of which are key biological processes implicated in AD. Moreover, our colocalization analysis revealed 32 genomic regions where shared genetic variants influenced both DNAm and dementia risk. Adjusting for age and other covariate variables, we found roughly one-third of aging-associated CpGs are also associated with AD or AD neuropathology in independent studies external to the ADNI and FHS datasets. Finally, we prioritized 9 aging-associated CpGs, located in promoter regions of PDE1B, ELOVL2, PODXL2, and other genomic regions, that showed strong positive blood-to-brain methylation concordance, as well as association with AD or AD neuropathology in independent studies, after adjusting for age and other covariates. Our findings provided insights into the functional overlap between the aging processes and AD, and nominated promising blood-based biomarkers for future AD research.
Longevity Relevance Analysis
(4)
The study identifies aging-associated DNA methylation changes in blood that overlap with Alzheimer's disease, suggesting potential blood-based biomarkers for AD research. The paper is relevant as it explores the biological mechanisms linking aging and Alzheimer's disease, which could contribute to understanding the root causes of age-related cognitive decline.
Rehman, A., Duffy, M., Gresova, K. ...
· genomics
· National Institute on Aging, NIH
· biorxiv
Aging is associated with increases in risk of multiple chronic diseases and at the cellular level, with disruptions in RNA homeostasis. Single-cell transcriptomic studies have revealed RNA abundance heterogeneity across brain cell types but the more complex changes in RNA process...
Aging is associated with increases in risk of multiple chronic diseases and at the cellular level, with disruptions in RNA homeostasis. Single-cell transcriptomic studies have revealed RNA abundance heterogeneity across brain cell types but the more complex changes in RNA processing such as alternative splicing, isoform usage, transcription start and polyadenylation site selection remain uncharacterized. Here, we combine single-cell analysis with long-read nanopore sequencing to capture full-length RNA isoforms and uncover temporal changes in RNA transcription, processing, and alternative splicing in the aging mouse cortex and hippocampus. By profiling transcriptomes from young adult to very old mice, we identify non-linear, cell-type-specific isoform expression changes and isoform usage shifts, primarily driven by transcription start site selection. These aging-associated isoform changes alter the coding potential and poly(A) site position of genes. Our data also reveal a high proportion of senescence in immune cells, far exceeding that of other cell types. We also identify isoform markers that, when applied to a machine learning model, distinguish senescent from normal immune cells. This study provides a full-length RNA isoform-based atlas of the aging mouse brain, offering insights into RNA metabolism remodeling across brain cell types throughout the lifespan.
Longevity Relevance Analysis
(4)
The study identifies cell-type-specific RNA isoform changes in the aging mouse brain that may contribute to understanding the molecular mechanisms of aging. This research is relevant as it explores the underlying processes of RNA metabolism remodeling associated with aging, which could inform strategies for addressing age-related decline.
Background The global aging population is increasingly inflicted with Alzheimer\'s disease (AD), but a cure is still unavailable. Neurotrophic Factor-1/carboxypeptidase E (NF-1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology AD mouse models Howev...
Background The global aging population is increasingly inflicted with Alzheimer\'s disease (AD), but a cure is still unavailable. Neurotrophic Factor-1/carboxypeptidase E (NF-1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology AD mouse models However, the mechanisms of action of NF-1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-1/CPE in AD mice. Methods AAV-human NF-1/CPE and a non-enzymatic form, NF-1/CPE -E342Q were delivered into hippocampus of 3xTg-AD mice and effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of hippocampus of 3xTg-AD mice with and without AAV-NF-1/CPE treatment was carried out. Results Hippocampal delivery of AAV-NF-1/CPE-E342Q prevented memory loss, neurodegeneration and increase in activated microglia in 3xTg-AD mice, indicating its action is independent of its enzymatic activity. Quantitative proteomic analysis of hippocampus of 3xTg-AD mice that underwent NF-1/CPE gene therapy revealed differential expression of >2000 proteins involving many metabolic pathways. Of these, two new proteins down-regulated by NF-1/CPE: Nexin4 (SNX4) and Trim28 which increase A{beta} production and tau levels, respectively were identified. Western blot analysis verified that they were reduced in AAV-NF-1/CPE treated 3xTg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as top signaling pathway altered as a response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3xTg-AD mice and were restored with AAV-NF-1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple proteins known to be markers of autophagy were down-regulated in 3xTg-AD mice, accounting for impaired autophagy. Expression of these proteins were upregulated in 3xTg-AD mice with NF-1/CPE gene therapy, thereby reversing autophagic impairment. Conclusions This study uncovered vast actions of NF-1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and A{beta} accumulation to reverse memory loss and AD pathology in 3xTg-AD mice. AAV-NF-1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment.
Longevity Relevance Analysis
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The paper claims that NF-1/CPE gene therapy can reverse neurodegeneration and cognitive decline in Alzheimer's disease models by regulating critical protein networks. This research is relevant as it explores a potential therapeutic approach that targets underlying mechanisms of neurodegeneration, which is a significant aspect of aging and age-related diseases.
Kim, M., Berger, C., Wolf, A. ...
· bioengineering
· Institute of Biological and Medical Imaging, Bioengineering Center, Helmholtz Zentrum Muenchen
· biorxiv
Adipose tissue plasticity and functional heterogeneity play a central role in maintaining energy homeostasis, and their malfunction leads to metabolic disorders such as obesity, diabetes, and cardiometabolic disease. Rapid, single-cell metabolic imaging of intact fat tissue not o...
Adipose tissue plasticity and functional heterogeneity play a central role in maintaining energy homeostasis, and their malfunction leads to metabolic disorders such as obesity, diabetes, and cardiometabolic disease. Rapid, single-cell metabolic imaging of intact fat tissue not only extends our understanding of metabolic dynamics and heterogeneity but also holds great potential as a tool for clinical diagnosis. However, the use of exogenous labels and dyes in conventional optical microscopy results in tissue deformation and requires time-consuming tissue preparation. Here, we demonstrated single-cell imaging of metabolic changes and heterogeneity in freshly excised adipose tissues that can distinguish tissue types without the need for exogenous labels using bond-specific, non-destructive, mid-infrared optoacoustic microscopy (MiROM) that allows preserving the native tissue architecture with minimal sample preparation time. Further leveraging MiROM, we monitored intracellular molecular and morphological changes during postnatal remodeling of adipose tissue when metabolic characteristics of adipocytes undergo a transient drastic change. Additionally, we developed an AI-based quantitative spatial tissue analysis tool (Q-SAT) to predict the spatial distribution of white fat- and brown fat-like features, providing a robust digital scoring method for adipose tissue phenotypic assessment. Collectively, we implemented MiROM as an enabling technology to provide fast, label-free metabolic imaging of unprocessed adipose tissue, opening a new perspective for understanding and characterizing the morpho-functional dynamics of adipose tissue remodeling.
Longevity Relevance Analysis
(4)
The paper demonstrates a novel method for single-cell metabolic imaging of adipose tissue that can enhance understanding of metabolic dynamics. This research is relevant as it addresses the plasticity and functional heterogeneity of adipose tissue, which are crucial factors in metabolic health and longevity.
Otto, D. J., Arriaga-Gomez, E., Thieme, E. ...
· bioinformatics
· Fred Hutchinson Cancer Center
· biorxiv
Kompot is a statistical framework for holistic comparison of multi-condition single-cell datasets, supporting both differential abundance and differential expression. Differential abundance captures changes in how cells populate the phenotypic manifold across conditions, while di...
Kompot is a statistical framework for holistic comparison of multi-condition single-cell datasets, supporting both differential abundance and differential expression. Differential abundance captures changes in how cells populate the phenotypic manifold across conditions, while differential expression identifies condition-specific changes in gene regulation that may be localized to particular regions of that manifold. Kompot models the distribution of cells and gene expression as continuous functions over a low-dimensional representation of cell states, enabling single-cell resolution inference with calibrated uncertainty estimates. Applying Kompot to aging murine bone marrow, we identified a continuum of shifts in hematopoietic stem cell and mature cell states, transcriptional remodeling of monocytes independent of compositional changes, and divergent regulation of oxidative stress response genes across cell types. By capturing both global and cell-state specific effects of perturbation, Kompot reveals how aging reshapes cellular identity and regulatory programs across the hematopoietic landscape. This framework is broadly applicable to dissecting condition-specific effects in complex single-cell landscapes.
Longevity Relevance Analysis
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The paper claims that the Kompot framework reveals how aging reshapes cellular identity and regulatory programs across the hematopoietic landscape. This research is relevant as it addresses the cellular and molecular changes associated with aging, contributing to the understanding of the biological mechanisms underlying aging and potential interventions.
Emily, M. F., Guillaud, L., De la Fuente Ruiz, S. ...
· neuroscience
· Okinawa Institute of Science and Technology
· biorxiv
Mitochondria are trafficked along axons and provide the energy required for several intracellular mechanisms including molecular transport and local translation, which is believed to contribute to the homeostasis of the axonal compartment. Decline in mitochondria activity is one ...
Mitochondria are trafficked along axons and provide the energy required for several intracellular mechanisms including molecular transport and local translation, which is believed to contribute to the homeostasis of the axonal compartment. Decline in mitochondria activity is one of the hallmarks of aging. It is still unclear, though, whether this decline corresponds to a concomitant reduction in the extent of axonal translation during aging. Using live cell imaging of sensory neurons, we found a significant decrease in the number of active mitochondria and the percentage of mitochondria localized to axons in aged mice compared to young mice. This decrease was mirrored by a loss of intracellular ATP as well as an ATP-dependent decrease in axoplasmic viscosity. In addition, the size of G3BP1 positive axonal granules and the number of FMRP axonal granules increased. Cumulatively, we found a functional decrease in the overall level of axonal translation in aged neurons. We were able to rescue this effect by increasing ATP synthesis, which induced a global decrease in axoplasmic viscosity, while promoting RNA granule solubilization and boosting axonal translation. Proteomic analysis of newly synthesized proteins in axons of aged vs young neurons revealed a dysregulation of pathways related to axonal biology and growth. We identified MAP1B and STAT3 as proteins whose axonal local synthesis was impaired in aged axons, and more notably show that this impairment could be rescued by increasing ATP synthesis. We believe that this research sheds light on axonal translation in aged neurons and its relationship with energy sources inside the axonal compartment, possibly presenting an opportunity for future therapeutics.
Longevity Relevance Analysis
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The paper claims that increasing ATP synthesis can rescue the impairment of axonal translation in aged neurons. This research is relevant as it addresses the decline in mitochondrial function and axonal translation during aging, potentially offering insights into the underlying mechanisms of aging and opportunities for therapeutic interventions.
Antonio Marino, Domenico Di Fraia, Diana Panfilova ...
· Ubiquitination
· Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany.
· pubmed
Post-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that...
Post-translational modifications (PTMs) regulate protein homeostasis, but how aging impacts PTMs remains unclear. Here, we used mass spectrometry to reveal changes in hundreds of protein ubiquitylation, acetylation, and phosphorylation sites in the mouse aging brain. We show that aging has a major impact on protein ubiquitylation. 29% of the quantified ubiquitylation sites were affected independently of protein abundance, indicating altered PTM stoichiometry. Using iPSC-derived neurons, we estimated that 35% of ubiquitylation changes observed in the aged brain can be attributed to reduced proteasome activity. Finally, we tested whether protein ubiquitylation in the brain can be influenced by dietary intervention. We found that one cycle of dietary restriction and re-feeding modifies the brain ubiquitylome, rescuing some but exacerbating other ubiquitylation changes observed in old brains. Our findings reveal an age-dependent ubiquitylation signature modifiable by dietary intervention, providing insights into mechanisms of protein homeostasis impairment and highlighting potential biomarkers of brain aging.
Longevity Relevance Analysis
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Aging significantly alters protein ubiquitylation in the mouse brain, and dietary interventions can modify these changes. The study addresses the mechanisms of protein homeostasis impairment related to aging, which is crucial for understanding the biological processes underlying longevity and age-related decline.
Dmitrii Usoltsev, Ekaterina Moguchaya, Maria Boyarinova ...
· Cardiovascular Diseases
· Almazov National Medical Research Centre, St. Petersburg, Russia.
· pubmed
Changes in the vascular system associated with aging contribute to conditions such as hypertension and atherosclerosis. In this study, we explored the prevalence and survival effects of vascular aging phenotypes in a Russian population, a group with a very high cardiovascular ris...
Changes in the vascular system associated with aging contribute to conditions such as hypertension and atherosclerosis. In this study, we explored the prevalence and survival effects of vascular aging phenotypes in a Russian population, a group with a very high cardiovascular risk according to the SCORE2 scale. A cohort of 618 participants from three metro areas underwent carotid-femoral pulse wave velocity (cfPWV) assessment between 2012 and 2018, with biannual follow-ups to record cardiovascular events and mortality. We compared our data with findings from previously published European cohorts to evaluate methods for classifying vascular aging phenotypes. Our findings indicate that definitions designed for low- and medium-risk populations are of limited use in high-risk groups. Moreover, the association between elevated cfPWV and increased overall mortality suggests a potential selection pressure on vascular aging phenotypes. These insights advance the development of predictive biomarkers for cardiovascular risk in populations with high rates of cardiovascular disease.
Longevity Relevance Analysis
(4)
The study suggests that current definitions of vascular aging phenotypes are inadequate for high cardiovascular risk populations, impacting mortality predictions. This research is relevant as it addresses the underlying mechanisms of vascular aging, which are critical to understanding and potentially mitigating age-related diseases.
Yuan Zhang, Huayu Wang, Fang Li ...
· Cellular Senescence
· Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
· pubmed
MRG15, a chromatin remodeling protein, plays a pivotal role in cellular senescence and proliferation. However, the precise roles and mechanisms of MRG15 in aging regulation remain unclear. Our research elucidates the distinct functions of MRG15's splice variants in aging. We find...
MRG15, a chromatin remodeling protein, plays a pivotal role in cellular senescence and proliferation. However, the precise roles and mechanisms of MRG15 in aging regulation remain unclear. Our research elucidates the distinct functions of MRG15's splice variants in aging. We find that MRG15L, contrary to the previously assumed MRG15S, accumulates with advancing age. Using histone peptide binding assays and protein interaction analysis, we demonstrate that MRG15L exhibits reduced affinity for histone H4 acetylation sites, thereby weakening CDK1 regulation, leading to G2/M phase arrest and promoting cellular senescence. During postnatal cardiac development, MRG15L expression increases and is linked to reduced regenerative capacity. Moreover, targeted knockout of MRG15L in mice enhances cardiac repair and regeneration following myocardial ischemia-reperfusion injury. These findings highlight MRG15L as a promising therapeutic target for age-related diseases, revealing its critical role in modulating aging pathways through alternative splicing.
Longevity Relevance Analysis
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MRG15L regulates CDK1 transcriptional activity, influencing cellular senescence and myocardial regeneration. The study addresses the mechanisms of aging through the role of alternative splicing in a chromatin remodeling protein, which is directly related to aging pathways and potential therapeutic targets for age-related diseases.
Xing-Yi Chen, Dong-Mei Wang, Ya Zhou ...
· Mitophagy
· Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Avenue, Wenjiang District, Chengdu, 611137, Sichuan, China.
· pubmed
Pulmonary fibrosis is often associated with aging, marked notably by the senescence of lung epithelial cells and the development of interstitial fibrosis. Mitophagy plays a crucial role in aging by degrading damaged mitochondria, thereby maintaining mitochondrial quality and cell...
Pulmonary fibrosis is often associated with aging, marked notably by the senescence of lung epithelial cells and the development of interstitial fibrosis. Mitophagy plays a crucial role in aging by degrading damaged mitochondria, thereby maintaining mitochondrial quality and cellular homeostasis. When mitophagy is disrupted or impaired, damaged mitochondria fail to be properly degraded by lysosomes. This results in the persistence of dysfunctional mitochondria, which can further damage cells, induce cell senescence and trigger inflammatory responses. These processes can worsen pulmonary fibrosis. Restoring proper mitophagy could be a promising strategy for managing pulmonary fibrosis and countering stress-induced premature cell senescence, potentially improving or even reversing lung function in aging lungs. This review will explore the complex relationship between cell senescence and pulmonary fibrosis, detailing the senescence characteristics in fibrotic lungs. It will also highlight recent advancements in understanding how mitophagy influences lung senescence and fibrosis and discuss potential therapeutic strategies to address mitophagy dysfunction in treating pulmonary fibrosis.
Longevity Relevance Analysis
(4)
Restoring proper mitophagy could improve or reverse lung function in aging lungs. The paper addresses the role of mitophagy in cell senescence and pulmonary fibrosis, which are directly related to the aging process and potential therapeutic strategies to mitigate age-related decline.
Watowich, M., Brassington, L., Longtin, A. ...
· epidemiology
· Vanderbilt University
· medrxiv
Declines in cardiometabolic health among older individuals are so ubiquitous in Western, high-income countries that non-communicable diseases (NCDs) like type 2 diabetes, hypertension, and cardiovascular disease have been termed "diseases of aging". In contrast, research from non...
Declines in cardiometabolic health among older individuals are so ubiquitous in Western, high-income countries that non-communicable diseases (NCDs) like type 2 diabetes, hypertension, and cardiovascular disease have been termed "diseases of aging". In contrast, research from non-industrial contexts has found low rates of cardiometabolic NCDs in old age, suggesting protective effects of lifestyle. To test if industrialization and urbanization generates or magnifies age-associated cardiometabolic health patterns, within-population analyses are needed. We worked with Turkana pastoralists of Kenya and Orang Asli mixed subsistence groups of Peninsular Malaysia-two groups that are transitioning from non-industrial to urban, market-integrated lifestyles. We find that rural, non-industrial environments produce minimal to modest age-dependent increases in body size, lipid, and blood pressure traits, and that urban environments significantly amplify age effects in repeatable ways across two distinct populations. However, we did not find that urban environments consistently accelerate biomarkers of more generalized functional capacity and biological aging, namely grip strength, walking speed, and epigenetic age. Together, these findings challenge the view that cardiometabolic "diseases of aging" are an intrinsic feature of aging, instead implicating urban lifestyle features as drivers of age-associated variation; however, these same lifestyle exposures may have heterogeneous effects on biological aging. These results underscore the urgency of understanding how rapid lifestyle changes shape aging trajectories, especially in populations undergoing industrial transitions.
Longevity Relevance Analysis
(4)
Urbanization exacerbates age-associated declines in cardiometabolic health among older individuals in transitioning populations. The paper is relevant as it explores how lifestyle changes due to urbanization impact aging trajectories and cardiometabolic health, addressing root causes rather than merely symptoms of aging.
Chia-Ling Kuo, Peiran Liu, Gabin Drouard ...
· Proteomics
· Department of Public Health Sciences, University of Connecticut Health Center, Farmington, CT 06032.
· pubmed
The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-ba...
The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-based signature of healthspan [healthspan proteomic score (HPS)] using proteomic data from the Olink Explore 3072 assay in the UK Biobank Pharma Proteomics Project (53,018 individuals and 2,920 proteins). A lower HPS was associated with higher mortality risk and several age-related conditions, such as chronic obstructive pulmonary disease, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to other biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. The external validity was evaluated using the Essential Hypertension Epigenetics study with proteomic data also from the Olink Explore 3072 and complementary epigenetic data, making it a valuable tool for assessing healthspan and as a potential surrogate marker to complement existing proteomic and epigenetic biological age measures in geroscience-guided studies.
Longevity Relevance Analysis
(5)
The paper claims that a proteomic signature (healthspan proteomic score) can predict mortality risk and age-related conditions more accurately than existing biological age measures. This research is relevant as it focuses on identifying biomarkers that could enhance healthspan, addressing the root causes of aging rather than merely treating age-related diseases.
de Lima Camillo, L. P., Gam, R., Maskalenka, K. ...
· cell biology
· Shift Bioscience Ltd
· biorxiv
Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: \"OSK(M)\") have been...
Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: \"OSK(M)\") have been shown to rejuvenate cells based on accurate predictors of age known as epigenetic clocks. Unfortunately, OSK(M) induces dangerous pluripotency pathways, making it unsuitable for therapeutic use. Recent work has focused on minimising the danger of the cocktail, but safety concerns remain. Here we present \"SB000\", the first single gene intervention to rejuvenate cells from multiple germ layers with efficacy rivalling the Yamanaka factors. Cells rejuvenated by SB000 retain their somatic identity, without evidence of pluripotency or loss of function. These results reveal that decoupling pluripotency from cell rejuvenation does not remove the ability to rejuvenate multiple cell types. This discovery paves the way for cell rejuvenation therapeutics that can be broadly applied across age-driven diseases.
Longevity Relevance Analysis
(5)
The paper claims that the single gene intervention "SB000" can rejuvenate cells from multiple germ layers without inducing pluripotency. This research is relevant as it addresses the root causes of aging by proposing a novel approach to cellular rejuvenation, potentially leading to therapies that combat age-related diseases.
Sadoughi, B., Hernandez-Rojas, R., Hamou, H. ...
· genomics
· Arizona State University
· biorxiv
Elucidating the socio-ecological factors that shape patterns of epigenetic modification in long-lived vertebrates is of broad interest to evolutionary biologists, geroscientists, and ecologists. However, aging research in wild populations is limited due to inability to measure ce...
Elucidating the socio-ecological factors that shape patterns of epigenetic modification in long-lived vertebrates is of broad interest to evolutionary biologists, geroscientists, and ecologists. However, aging research in wild populations is limited due to inability to measure cellular hallmarks of aging noninvasively. Here, we demonstrate that cellular DNA methylation (DNAm) profiles from fecal samples provide an accurate and reliable molecular clock in wild capuchin monkeys. Analysis of blood, feces, and urine samples from a closely related species shows that DNAm differentiates between species and different types of biological samples. We further find age-associated differences in DNAm relevant to cellular damage, inflammation, and senescence, consistent with hallmarks conserved across humans and other mammalian species, speaking to the comparative potential. By demonstrating that DNAm can be studied non-invasively in wild animals, our research opens new avenues in the study of modifiers of the pace of aging, and increases potential for cross-population and species comparisons.
Longevity Relevance Analysis
(5)
The paper claims that non-invasive DNA methylation profiles from fecal samples can serve as a reliable molecular clock for aging in wild capuchin monkeys. This research is relevant as it explores the molecular mechanisms of aging and provides a novel method for studying aging in natural populations, which could lead to insights into the root causes of aging and its modifiers.
Shemtov, S. J., McGann, E., Carrillo, L. ...
· molecular biology
· University of Southern California
· biorxiv
Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most ...
Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.
Longevity Relevance Analysis
(5)
Reduced IGF-1 signaling's pro-longevity effects are contingent on mitochondrial genome stability. This paper is relevant as it explores the mechanisms underlying lifespan extension and the critical role of mitochondrial integrity in aging.
Soe Maung Maung Phone Myint, Alexander Tate Lasher, Kaimao Liu ...
· Aging cell
· Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
· pubmed
Multiple studies in mice with genetically disrupted growth hormone (GH) signaling have demonstrated that such disruption results in reduced body size, robustly increased longevity (> 50% in some cases), and improvements across multiple health parameters. However, it remains uncle...
Multiple studies in mice with genetically disrupted growth hormone (GH) signaling have demonstrated that such disruption results in reduced body size, robustly increased longevity (> 50% in some cases), and improvements across multiple health parameters. However, it remains unclear how generalizable these findings are across mammals. Evidence in rats is limited and inconsistent. These conflicting results highlight the need for further investigation into the role of GH signaling in longevity across species. To address this gap, we developed a novel GH-deficient rat model using CRISPR/Cas9 technology to introduce a 10 bp deletion in exon 3 of the gene encoding rat GH-releasing hormone (GHRH) yielding a non-functional GHRH product. Physiological characterization of GHRH knockout (KO) rats revealed that they were half the body weight of wild-type controls. Additionally, relative to controls, they displayed an increased percent body fat, enhanced insulin sensitivity, reduced circulating insulin-like growth factor I (IGF-I) concentration, and a decreased reliance on glucose oxidation for energy metabolism, as determined by indirect calorimetry. Analysis of the gut microbial community in adult GHRH-KO rats further revealed a less diverse male microbiome, but a more diverse female KO microbiome compared to controls. Collectively, these findings demonstrate that multiple aspects of the GH activity-deficient phenotype, well-documented in mice, are faithfully recapitulated in our rat model. Therefore, the GHRH-deficient rat model represents a valuable new tool for advancing our understanding of the role of GH signaling in aging processes.
Longevity Relevance Analysis
(4)
The paper claims that a novel GH-deficient rat model recapitulates key aspects of growth hormone signaling's role in aging. This research is relevant as it explores the underlying mechanisms of aging through genetic manipulation, potentially offering insights into longevity across species.
Sturmlechner, I., Jain, A., Jiang, J. ...
· immunology
· Mayo Clinic
· biorxiv
Older adults are susceptible to infections, in part due to waning of immune memory. To determine mechanisms that determine long-lasting versus short-term immunity, we examined varicella zoster virus (VZV) vaccination as a model system. We contrasted VZV antigen-specific T cells s...
Older adults are susceptible to infections, in part due to waning of immune memory. To determine mechanisms that determine long-lasting versus short-term immunity, we examined varicella zoster virus (VZV) vaccination as a model system. We contrasted VZV antigen-specific T cells several years after vaccination in adults who had been vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine that confers durable protection only when given at young age, or with an adjuvanted VZV component vaccine that elicits effective, long-lasting immunity in older adults. CD8+ T cells were highly sensitive to age-related changes showing T cell subset shifts, loss in TCR diversity and reduced stem-like features while gaining NK-like signatures without evidence for cellular senescence or exhaustion. VZV-specific CD4+ T cells were largely resilient to age and maintained phenotypic and TCR diversity. Immunization of older adults with the adjuvanted VZV vaccine did not reverse age-associated defects in CD8+ T cells. Instead, it selectively improved the functionality of VZV-specific Th17 CD4+ T cells and prevented their acquisition of Treg features, likely as consequence of lipid metabolic pathways. Collectively, our data indicate that effective vaccination in older adults is supported by the generation of a durable, antigen-specific CD4+ Th17 population that resists mis-differentiation into Tregs and that compensates for age-related defects in CD8+ T cells.
Longevity Relevance Analysis
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The paper claims that antigen-specific Th17 CD4+ T cells can improve immune responses in older adults by offsetting age-related defects in CD8+ T cells. This research is relevant as it explores mechanisms to enhance immune memory and functionality in aging, addressing a root cause of susceptibility to infections in older populations.
Ming Ann Sim, Jorming Goh, Jasinda Lee ...
· Sirolimus
· Centre for Healthy Longevity, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
· pubmed
The geroprotective effects of rapamycin in mitigating frailty and cognitive complications in the perioperative period remains unknown. Of 39 C57BL/6 mice tested, 19 were young (16 weeks), and 20 were old (80 weeks). The interventional group (10 old, 10 young) received daily oral ...
The geroprotective effects of rapamycin in mitigating frailty and cognitive complications in the perioperative period remains unknown. Of 39 C57BL/6 mice tested, 19 were young (16 weeks), and 20 were old (80 weeks). The interventional group (10 old, 10 young) received daily oral rapamycin for 8 weeks pre-op compared to controls (10 old, 9 young). Sham laparotomy was performed at week 9. Perioperative frailty was assessed using a murine clinical frailty scale, preoperatively and at 1, 4 and 8 weeks postoperatively. Spatial memory was assessed using the Barnes maze preoperatively, and at weeks 1 and 4 post-op. Rapamycin treatment is associated with significantly less decline in postoperative clinical frailty(p < 0.05). Subgroup analysis revealed similar findings for old and young mice. The rapamycin group demonstrated improved cognitive performance at 1-week postoperatively (β 40.18, 95%C.I. 8.70-71.67, p = 0.012), but only in older mice (β 54.51, 95%C.I. 6.77-102.25, p = 0.025). In a pre-clinical animal model of anesthesia and surgery, rapamycin supplementation protected against surgery-induced frailty and short-term postoperative cognitive dysfunction.
Longevity Relevance Analysis
(4)
Rapamycin supplementation mitigates perioperative frailty and cognitive decline in a murine model. The study addresses the potential geroprotective effects of rapamycin, which is directly related to understanding and potentially intervening in the aging process.
Jia Xie, Ze-Guang Han
· BioEssays : news and reviews in molecular, cellular and developmental biology
· Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
· pubmed
Heterochromatin, a crucial constituent of the eukaryotic nucleus with highly conserved and transcriptionally silenced characteristics, plays a pivotal role in safeguarding genome stability, regulating nuclear morphology, and mediating cell fate. Recent convincing evidence indicat...
Heterochromatin, a crucial constituent of the eukaryotic nucleus with highly conserved and transcriptionally silenced characteristics, plays a pivotal role in safeguarding genome stability, regulating nuclear morphology, and mediating cell fate. Recent convincing evidence indicates that the formation and maintenance of heterochromatin are implicated in cellular senescence and age-associated disorders. Interestingly, an attractive mechanism involving liquid-liquid phase separation (LLPS) may exert a central role in regulating heterochromatin formation and maintenance. In this review, we provide an overview of recent research to illustrate the role and regulatory mechanism of the biomolecular condensates in the regulation of heterochromatin stabilization. In addition, we elucidate how heterochromatin loss contributes to cellular senescence by triggering genome instability, and explore the potential therapeutic strategies to counteract cellular senescence and age-related pathologies by restoring heterochromatin stability. Finally, we outline current research challenges and future directions aimed at achieving a more comprehensive understanding of the link among heterochromatin regulation, phase separation, and cellular senescence, for ameliorating the effects of ageing in the future.
Longevity Relevance Analysis
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The paper discusses the role of biomolecular condensates in stabilizing heterochromatin and their implications for cellular senescence and age-related pathologies. This research is relevant as it addresses mechanisms that could potentially mitigate the root causes of aging and cellular decline.
Rychlicka-Buniowska, E., Sarkisyan, D., Horbacz, M. ...
· genetic and genomic medicine
· Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; 3P-Medicine Laboratory, Medical Universit
· medrxiv
Loss of Y chromosome (LOY) and clonal hematopoiesis of indeterminate potential (CHIP) are common age-related events associated with multiple adverse outcomes in the elderly. While LOY has been associated with higher risk of Alzheimer disease (AD), CHIP has been suggested to perfo...
Loss of Y chromosome (LOY) and clonal hematopoiesis of indeterminate potential (CHIP) are common age-related events associated with multiple adverse outcomes in the elderly. While LOY has been associated with higher risk of Alzheimer disease (AD), CHIP has been suggested to perform a protective role against AD. Moreover, the co-occurrence of CHIP and LOY is debated. We performed deep whole-exome sequencing of FACS-isolated CD4T lymphocytes, NK and myeloid cells from men with AD and controls exhibiting either LOY or retention of Y chromosome (ROY). We found 39 sequence variants in known (canonical) myeloid driver genes of clonal hematopoiesis (MD-CH) and known lymphoid driver genes (LD-CH), and maximally 14(35%) of these could co-exist with LOY within the same clone. We further describe 192 unknown drivers of clonal hematopoiesis (UD-CH), which were markedly enriched in AD-LOY individuals (odds ratio=4.8, Benjamini-Hochberg adjustedp=0.041), and over 20% of these variants were protein-truncating. In myeloid cells, the total burden of all detected drivers correlated with the percentage of LOY cells (Spearman{rho}=0.52, adjustedp=0.00041). In conclusion, our findings suggest that LOY acts as the primary driver of clonal hematopoiesis in AD by seeding myeloid clones. These clones may subsequently accumulate additional, often truncating, UD variants, while most canonical CHIP mutations arise independently of LOY. Our study delineates distinct yet partially overlapping clonal architectures for LOY and CHIP in late-onset AD and underscores LOY-driven myeloid expansion as a potential contributor to disease pathogenesis.
Longevity Relevance Analysis
(4)
The paper claims that loss of Y chromosome (LOY) drives clonal hematopoiesis in Alzheimer disease (AD) by seeding myeloid clones that may contribute to disease pathogenesis. This research is relevant as it explores the underlying mechanisms of age-related diseases, specifically how genetic factors like LOY may influence the progression of Alzheimer's, thereby addressing potential root causes of aging-related pathologies.
McQuade, A., Castillo, V. C., Hagan, V. ...
· neuroscience
· University of California, San Francisco
· biorxiv
Microglia dynamically support brain homeostasis through the induction of specialized activation programs or states. One such program is the Interferon-Responsive Microglia state (IRM), which has been identified in developmental windows, aging, and disease. While the functional im...
Microglia dynamically support brain homeostasis through the induction of specialized activation programs or states. One such program is the Interferon-Responsive Microglia state (IRM), which has been identified in developmental windows, aging, and disease. While the functional importance of this state is becoming increasingly clear, our understanding of the regulatory networks that govern IRM induction remain incomplete. To systematically identify genetic regulators of the IRM state, we conducted a genome-wide CRISPR interference (CRISPRi) screen in human iPSC-derived microglia (iPS-Microglia) using IFIT1 as a representative IRM marker. We identified 772 genes that modulate IRM, including canonical type I interferon signaling genes (IFNAR2, TYK2, STAT1/2, USP18) and novel regulators. We uncovered a non-canonical role for the CCR4-NOT complex subunit CNOT10 in IRM activation, independent of its traditional function. This work provides a comprehensive resource for dissecting IRM biology and highlights both established and novel targets for modulating microglial interferon signaling in health and disease.
Longevity Relevance Analysis
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The paper identifies genetic regulators of the Interferon-Responsive Microglia state, which is implicated in aging and disease. Understanding the regulatory networks of microglia in the context of aging could provide insights into the mechanisms of age-related neurodegeneration and potential interventions.
Palomares, D., Vanparys, A., Jorgji, J. ...
· neuroscience
· Aging and Dementia group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium
· biorxiv
Background: Although the connection between aging and neurodegenerative pathologies like Alzheimer\'s disease (AD) has long been recognized, the underlying pathological mechanisms remain largely unknown. Senescent brain cells build up in the brains of AD patients and a causal lin...
Background: Although the connection between aging and neurodegenerative pathologies like Alzheimer\'s disease (AD) has long been recognized, the underlying pathological mechanisms remain largely unknown. Senescent brain cells build up in the brains of AD patients and a causal link has been established between senescence and AD-related tauopathy. Methods: To investigate the role of cellular senescence in tau-mediated neuropathology, we crossed the Terc knockout (Terc-/-) senescent mouse model with the P301S tauopathy model (PS19 line). Using brain sections and protein extracts, we employed Western blot and immunostaining analyses to investigate the expression of tau-related neuropathological features within a senescent context. Results: We found that the brains of 6- and 9-month-old Terc-/- mice exhibit significant telomere attrition and signs of cellular senescence. Introducing a senescent phenotype in a tauopathy mouse model resulted in increased tau phosphorylation at key residues, particularly in the hippocampus. Over time, this was associated with enhanced tau truncation and aggregation. These pathological changes were accompanied by exacerbated astrocyte and microglial activation, as well as selective neuronal loss in vulnerable brain regions. Conclusions: Overall, our findings place senescence as a key upstream regulator of tau pathology, suggesting that targeting senescent cells and their detrimental effects may offer promising therapeutic strategies for AD and other related tauopathies.
Longevity Relevance Analysis
(4)
The paper claims that cellular senescence is a key upstream regulator of tau pathology in neurodegeneration. This research is relevant as it explores the underlying mechanisms of aging-related neurodegenerative diseases and suggests potential therapeutic strategies targeting senescent cells, addressing root causes of aging rather than merely treating symptoms.
Hiroshi Kobayashi, Shogo Imanaka
· DNA, Mitochondrial
· Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara, Nara 634‑0813, Japan.
· pubmed
Mitochondria and mitochondrial DNA (mtDNA) are crucial for cellular energy metabolism and the adaptive response to environmental changes. mtDNA collaborates with the nuclear genome to regulate mitochondrial function. Dysfunctional mitochondria and mutations in mtDNA are implicate...
Mitochondria and mitochondrial DNA (mtDNA) are crucial for cellular energy metabolism and the adaptive response to environmental changes. mtDNA collaborates with the nuclear genome to regulate mitochondrial function. Dysfunctional mitochondria and mutations in mtDNA are implicated in a wide range of diseases, including mitochondrial disorders, neurodegenerative conditions, age‑associated pathologies and cancer. While the nuclear genome has been extensively studied for its role in driving the clonal expansion of oncogenes and other aging‑related genetic alterations, knowledge regarding mtDNA remains comparatively limited. However, advances in quantitative analysis have provided information regarding the complex patterns of mtDNA mutations. The present review offers a detailed examination of mtDNA mutations and their classifications in the contexts of aging and cancer, and elucidates the role of mtDNA mutations in these processes. Mutations in mtDNA can be detected as early as the neonatal stage, yet most transition mutations retain a normal cellular phenotype. In contrast to mutations in oncogenes and tumor suppressor genes within the nuclear genome, mtDNA exhibits conserved mutational signatures, irrespective of cancer tissue origin. To adapt to the aging process, mitochondria undergo clonal expansion of advantageous mtDNA mutations, maintaining a dynamic equilibrium among various mitochondrial clones. Over time, however, the loss of strand bias can disrupt this equilibrium, diminishing the pool of adaptive clones. This breakdown in mitochondrial homeostasis may contribute to tumorigenesis. In conclusion, the heterogeneity of mtDNA mutations and the collapse of its homeostasis are pivotal in the progression of age‑related diseases, including cancer, underscoring the importance of mtDNA mutations in health and disease.
Longevity Relevance Analysis
(4)
Mitochondrial DNA mutations play a significant role in the aging process and cancer development. The paper discusses the implications of mtDNA mutations in age-related diseases, addressing underlying mechanisms that contribute to aging rather than merely treating symptoms.
Matías Fuentealba, Laure Rouch, Sophie Guyonnet ...
· Nature aging
· Buck AI Platform, Buck Institute for Research on Aging, Novato, CA, USA.
· pubmed
Age-related decline in intrinsic capacity (IC), defined as the sum of an individual's physical and mental capacities, is a cornerstone for promoting healthy aging by prioritizing maintenance of function over disease treatment. However, assessing IC is resource-intensive, and the ...
Age-related decline in intrinsic capacity (IC), defined as the sum of an individual's physical and mental capacities, is a cornerstone for promoting healthy aging by prioritizing maintenance of function over disease treatment. However, assessing IC is resource-intensive, and the molecular and cellular bases of its decline are poorly understood. Here we used the INSPIRE-T cohort (1,014 individuals aged 20-102 years) to construct the IC clock, a DNA methylation-based predictor of IC, trained on the clinical evaluation of cognition, locomotion, psychological well-being, sensory abilities and vitality. In the Framingham Heart Study, DNA methylation IC outperforms first-generation and second-generation epigenetic clocks in predicting all-cause mortality, and it is strongly associated with changes in molecular and cellular immune and inflammatory biomarkers, functional and clinical endpoints, health risk factors and lifestyle choices. These findings establish the IC clock as a validated tool bridging molecular readouts of aging and clinical assessments of IC.
Longevity Relevance Analysis
(5)
The paper claims that a blood-based epigenetic clock can predict intrinsic capacity and mortality, linking molecular aging markers to clinical assessments. This research is relevant as it addresses the underlying mechanisms of aging and intrinsic capacity, which are crucial for promoting healthy aging and understanding the biological basis of longevity.
Mareike Peters, Patric Teodorescu, Sergiu Pasca ...
· Haematologica
· Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.
· pubmed
Not available.
Not available.
Longevity Relevance Analysis
(4)
The paper claims to comprehensively characterize age-related changes in the human bone marrow microenvironment. This research is relevant as it addresses the biological changes associated with aging, which could provide insights into the underlying mechanisms of aging and potential interventions.
Xiao-Wei Liu, Hao-Wei Xu, Shu-Bao Zhang ...
· Cell death discovery
· Department of Spinal Surgery, Shanghai East Hospital, School of Medicine, Tongji University, 200092, Shanghai, China.
· pubmed
Intervertebral disc degeneration (IVDD) is a common pathology involving various degenerative diseases of the spine, with nucleus pulposus cell (NPC) senescence playing an important role in its pathogenesis. Transcriptional and epigenetic processes have been increasingly implicate...
Intervertebral disc degeneration (IVDD) is a common pathology involving various degenerative diseases of the spine, with nucleus pulposus cell (NPC) senescence playing an important role in its pathogenesis. Transcriptional and epigenetic processes have been increasingly implicated in aging and longevity. E74-like factor 1 (ELF1) is a member of the erythroblast transformation specific family of proteins, which induce gene transcription by binding to gene promoters or enhancer sequences. However, the role of ELF1 in age-related diseases is unclear, with no reports of its involvement in NPC senescence or IVDD. ELF1 expression levels were assessed in human NP samples from IVDD patients, IVDD animal models, and naturally aged NP samples. Adeno-associated virus 5 (AAV5) vector-mediated Elf1 overexpressing mice and Elf1 knockout (KO) mice were used to investigate its role in NPC senescence and IVDD in vivo. The m6A methylase METTL3 and reading protein YTHDF2 were identified as downstream effectors of ELF1 using proteomic sequencing, RNA sequencing, ChIP-seq, promoter prediction, and binding analyses. MepRIP-qPCR, RNA pulldown, and double luciferase point mutation experiments revealed that METTL3 and YTHDF2 can recognize the m6A site on E2F3 mRNA, a key cell cycle gene. Finally, virtual screening techniques and various experiments were used to identify small molecule targets for ELF1 inhibition. ELF1 was found to drive m6A modification changes during NPC aging. The small molecule mycophenolate mofetil (MMF) could successfully target and inhibit ELF1 expression. In senescent NPCs, ELF1 can bind to the METTL3 and YTHDF2 gene promoter regions. Overexpressing METTL3 increased the E2F3 mRNA m6A modification abundance, while YTHDF2 was recruited to recognize this m6A site. This can accelerate the E2F3 mRNA degradation rate and ultimately lead to the onset of G1/S cell cycle arrest in NPC. For the first time, the transcription factor ELF1 has been identified as a novel regulator of NPC senescence and IVDD, which involves the ELF1-METTL3/YTHDF2-m6A-E2F3 axis. MMF, a small molecule designed to inhibit ELF1 and delay NPC senescence, was screened for the first time. This can potentially lead to new epigenetic therapeutic strategies for drug discovery and development for the clinical treatment of IVDD.
Longevity Relevance Analysis
(4)
The paper identifies ELF1 as a novel regulator of nucleus pulposus cell senescence and intervertebral disc degeneration through the ELF1-METTL3/YTHDF2-m6A-E2F3 axis. This research is relevant as it explores the underlying mechanisms of cellular senescence, which is a key factor in aging and age-related diseases, potentially leading to therapeutic strategies that address the root causes of aging.
Rooban Sivakumar, K A Arul Senghor, V M Vinodhini ...
· Drugs & aging
· Department of Biochemistry, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, Kanchipuram, Chennai, Tamil Nadu, 603203, India. [email protected].
· pubmed
Metformin, traditionally promoted for its efficacy in diabetes, is increasingly appreciated for its geroprotective potential in the development of vascular aging, a key contributor to cardiovascular morbidity. This review aims at understanding the spectrum of mechanisms that gove...
Metformin, traditionally promoted for its efficacy in diabetes, is increasingly appreciated for its geroprotective potential in the development of vascular aging, a key contributor to cardiovascular morbidity. This review aims at understanding the spectrum of mechanisms that govern the amelioration of degenerative processes associated with vascular aging by metformin. Central to this therapeutic promise is the activation of AMPK, which reduces metabolic dysregulation and hence slows vascular senescence. Oxidative stress has been identified as an important mechanism thought to be enhanced by metformin in the preservation of endothelial function and attenuation of arterial stiffening. Besides, metformin has lipid-lowering and antiinflammatory activity, which is critical for reducing arterial rigidity and the development of atherosclerotic plaque. In recent times, both clinical and preclinical studies revealed empirical data that confirmed the effectiveness of metformin in the improvement of endothelial function and the decreasing of arterial stiffness as a part of a reduction in the rates of cardiovascular events. The therapeutic action of the drug goes beyond glycemic control, rendering it a geroprotector potentially suitable for broader application in age-related vascular decline. In light of these findings, the clinical acceptance of metformin as an intervention in vascular aging should be possible and promising. Carefully monitored follow-up studies are needed to optimize dosing, delineate the broad biological effects, and verify long-term benefits, which will underpin metformin's role in the paradigm against age-associated vascular diseases.
Longevity Relevance Analysis
(4)
Metformin may serve as a geroprotector by ameliorating vascular aging through mechanisms such as AMPK activation and reduction of oxidative stress. The paper addresses the potential of metformin to target underlying mechanisms of aging rather than merely treating age-related symptoms, aligning with longevity research goals.
Jackson Nuss, Matt Kaeberlein, Alessandro Bitto ...
· GeroScience
· Department of Laboratory Medicine & Pathology, School of Medicine, University of Washington, Seattle, WA, USA.
· pubmed
Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the p...
Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the pathophysiology of mitochondrial disease and mitochondrial dysfunction in sporadic disorders. Intriguingly, longevity interventions are very effective at treating symptoms of disease in this model. Herein, we introduce the model and its notable features that may help provide insights in longevity research. We performed a retrospective analysis of historical data from our laboratories over the past 10 years regarding the use of this animal model in aging studies, the manifestation and progression of mitochondrial disease, and factors that influence their premature death. We observed a correlation between weight and lifespan in female animals and a sex-independent correlation between the onset of clasping, a typical neurodegenerative symptom, and overall survival. We observed a sexual dimorphism in lifespan with female mice being more resilient despite a similar age of onset of disease symptoms. Lastly, we report increased lifespan and delayed onset of disease symptoms following treatment with 17-alpha-estradiol, a non-feminizing estrogen which can extend lifespan in genetically heterogeneous mice. This analysis serves as a useful guide for researchers utilizing this animal in the discovery of effective interventions for longevity and to prevent the onset of disease. It suggests there may be unprecedented underlying sex-specific differences in patients with Leigh syndrome and further strengthens the connection between normative aging and mitochondrial dysfunction.
Longevity Relevance Analysis
(4)
The paper claims that treatment with 17-alpha-estradiol can increase lifespan and delay disease onset in a mouse model of Leigh syndrome. This research is relevant as it explores potential interventions that may address underlying mechanisms of aging and mitochondrial dysfunction, contributing to the understanding of longevity.
Jing, Y., Li, L., Guo, W. ...
· cell biology
· Department of Urology, Shanghai General 32 Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 33 200080, China
· biorxiv
Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to...
Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to stromal cell accumulation in BPH. Using single-cell transcriptomic analysis, endothelial lineage tracing in mice, and validation in human samples, we showed that senescence-associated mast cells increased the expression of vascular endothelial growth factor A (VEGFA) and transforming growth factor-beta 1 (TGF-{beta}1) through the stem cell factor (SCF)/c-KIT-MAPK-JUND signaling pathway, thereby inducing EndMT in endothelial progenitor cells. Stromal fibroblasts express SCF, promoting mast cell activation and establishing a feedback loop that supports continued stromal proliferation. Intriguingly, inhibition of mast cell activation reduces EndMT and attenuates prostate enlargement in vivo.Thus, these findings revealed a senescence-linked immune - stromal interaction in the aging prostate and identify potential targets for therapeutic intervention in BPH.
Longevity Relevance Analysis
(4)
Senescent mast cells promote endothelial-to-mesenchymal transition in benign prostatic hyperplasia through the SCF/c-KIT signaling pathway. This study addresses the role of cellular senescence in a specific age-related condition, linking immune responses to stromal changes, which could inform therapeutic strategies targeting aging mechanisms.