Valentin Flietner, Bernd Heidergott, Frank den Hollander ...
· Aging
· PwC, Bernhard-Wicki-Strasse 8, 80636, Munich, Germany.
· pubmed
In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modelling of network evolutio...
In this paper, we advance the network theory of aging and mortality by developing a causal mathematical model for the mortality rate. First, we show that in large networks, where health deficits accumulate at nodes representing health indicators, the modelling of network evolution with Poisson processes is universal and can be derived from fundamental principles. Second, with the help of two simplifying approximations, which we refer to as mean-field assumption and homogeneity assumption, we provide an analytical derivation of Gompertz law under generic and biologically relevant conditions. Third, we identify for which network parameters Gompertz law is accurate, express the parameters in Gompertz law as a function of the network parameters, and illustrate our computations with simulations and analytic approximations. Our paper is the first to offer a full mathematical explanation of Gompertz law and its limitations based on network theory.
Longevity Relevance Analysis
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The paper presents a mathematical model that explains Gompertz law in the context of aging and mortality through network theory. This work is relevant as it addresses fundamental aspects of aging and mortality, potentially contributing to a deeper understanding of the biological processes underlying aging.
Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at...
Aging increases the risk of developing fibrotic diseases by hampering tissue regeneration after injury. Using longitudinal single-cell RNA-seq and spatial transcriptomics, here we compare the transcriptome of bleomycin (BLM) -induced fibrotic lungs of young and aged male mice, at 3 time points corresponding to the peak of fibrosis, regeneration, and resolution. We find that lung injury shifts the transcriptomic profiles of three pulmonary capillary endothelial cells (PCEC) subpopulations. The associated signatures are linked to pro-angiogenic signaling with strong Lrg1 expression and do not progress similarly throughout the resolution process between young and old animals. Moreover, part of this set of resolution-associated markers is also detected in PCEC from samples of patients with idiopathic pulmonary fibrosis. Finally, we find that aging also alters the transcriptome of PCEC, which displays typical pro-fibrotic and pro-inflammatory features. We propose that age-associated alterations in specific PCEC subpopulations may interfere with the process of lung progenitor differentiation, thus contributing to the persistent fibrotic process typical of human pathology.
Longevity Relevance Analysis
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Aging alters the transcriptome of pulmonary capillary endothelial cells, impacting their role in lung injury resolution and fibrosis. The study addresses age-related changes in cellular mechanisms that contribute to fibrotic diseases, which is relevant to understanding the biological processes of aging and potential interventions.
Yichu Fu, Binhan Wang, Aqu Alu ...
· Signal Transduction
· College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, China.
· pubmed
Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immun...
Immunosenescence refers to the abnormal activation or dysfunction of the immune system as people age. Inflammaging is a typical pathological inflammatory state associated with immunosenescence and is characterized by excessive expression of proinflammatory cytokines in aged immune cells. Chronic inflammation contributes to a variety of age-related diseases, such as neurodegenerative disease, cancer, infectious disease, and autoimmune diseases. Although not fully understood, recent studies contribute greatly to uncovering the underlying mechanisms of immunosenescence at the molecular and cellular levels. Immunosenescence is associated with dysregulated signaling pathways (e.g., overactivation of the NF-κB signaling pathway and downregulation of the melatonin signaling pathway) and abnormal immune cell responses with functional alterations and phenotypic shifts. These advances remarkably promote the development of countermeasures against immunosenescence for the treatment of age-related diseases. Some anti-immunosenescence treatments have already shown promising results in clinical trials. In this review, we discuss the molecular and cellular mechanisms of immunosenescence and summarize the critical role of immunosenescence in the pathogenesis of age-related diseases. Potential interventions to mitigate immunosenescence, including reshaping immune organs, targeting different immune cells or signaling pathways, and nutritional and lifestyle interventions, are summarized. Some treatment strategies have already launched into clinical trials. This study aims to provide a systematic and comprehensive introduction to the basic and clinical research progress of immunosenescence, thus accelerating research on immunosenescence in related diseases and promoting the development of targeted therapy.
Longevity Relevance Analysis
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The paper discusses the mechanisms of immunosenescence and potential interventions to mitigate its effects on age-related diseases. This research is relevant as it addresses the underlying causes of aging-related immune dysfunction, which is crucial for developing strategies to promote longevity and improve healthspan.
Nazma Malik, Reuben J Shaw
· Annual review of cell and developmental biology
· 1Metabolism in Immunity, Cancer & Aging Group, MRC Laboratory of Medical Sciences, Imperial College London, London, United Kingdom; email: [email protected].
· pubmed
Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of euk...
Cells must constantly adapt their metabolism to the availability of nutrients and signals from their environment. Under conditions of limited nutrients, cells need to reprogram their metabolism to rely on internal stores of glucose and lipid metabolites. From the emergence of eukaryotes to the mitochondria as the central source of ATP to hundreds of other metabolites required for cellular homeostasis, survival, and proliferation, cells had to evolve sensors to detect even modest changes in mitochondrial function in order to safeguard cellular integrity and prevent energetic catastrophe. Homologs of AMP-activated protein kinase (AMPK) are found in all eukaryotic species and serve as an ancient sensor of conditions of low cellular energy. Here we explore advances in how AMPK modulates core processes underpinning the mitochondrial life cycle and how it serves to restore mitochondrial health in parallel with other beneficial metabolic adaptations.
Longevity Relevance Analysis
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The paper claims that AMPK modulates mitochondrial health and metabolic adaptations. The focus on AMPK as a central regulator of energy metabolism and mitochondrial function is relevant to understanding the mechanisms of aging and potential interventions for longevity.
Amin Haghani, Ake T Lu, Qi Yan ...
· GeroScience
· Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. [email protected].
· pubmed
Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigeneti...
Several widely used epigenetic clocks have been developed for mice and other species, but a persistent challenge remains: different mouse clocks often yield inconsistent results. To address this limitation in robustness, we present EnsembleAge, a suite of ensemble-based epigenetic clocks. Leveraging data from over 200 perturbation experiments across multiple tissues, EnsembleAge integrates predictions from multiple penalized models. Empirical evaluations demonstrate that EnsembleAge outperforms existing clocks in detecting both pro-aging and rejuvenating interventions. Furthermore, we introduce EnsembleAge HumanMouse, an extension that enables cross-species analyses, facilitating translational research between mouse models and human studies. Together, these advances underscore the potential of EnsembleAge as a robust tool for identifying and validating interventions that modulate biological aging.
Longevity Relevance Analysis
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EnsembleAge demonstrates that integrating multiple epigenetic clocks can improve the assessment of biological aging and intervention effects. This paper is relevant as it addresses the root causes of aging by providing a robust tool for identifying and validating interventions that modulate biological aging.
Mishra, M., Kim, H.-H., Youm, Y.-H. ...
· physiology
· Yale School of Medicine
· biorxiv
Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower ...
Caloric restriction (CR) extends lifespan, yet the convergent immunometabolic mechanism of healthspan remains unclear. Using longitudinal plasma proteomics analyses in humans achieving 14% CR for 2 years, we identified that inhibition of the complement pathway is linked to lower inflammaging. The protein C3a (and its cleaved form) was significantly lowered by CR, thus reducing inflammation emanating from three canonical complement pathways. Interestingly, circulating C3a levels are increased during aging in mice, with visceral adipose tissue macrophages as the predominant source. In macrophages, C3a signaling via ERK elevated inflammatory cytokine production, suggesting the existence of an autocrine loop that promotes inflammaging. Notably, long-lived FGF21-overexpressing mice and PLA2G7-deficient mice exhibited lower C3a in aging. Specific small molecule-mediated systemic C3 inhibition reduced inflammaging, improved metabolic homeostasis, and enhanced healthspan of aged mice. Collectively, our findings reveal that complement C3 deactivation is a metabolically regulated inflammaging checkpoint that can be harnessed to extend healthspan.
Longevity Relevance Analysis
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The paper claims that complement C3 deactivation is a metabolically regulated checkpoint that reduces inflammaging and can extend healthspan. This research is relevant as it addresses a potential mechanism underlying aging and healthspan extension through immunometabolic pathways, rather than merely treating age-related diseases.
Peng Li, Yi Yang, Xiang Qin ...
· Research (Washington, D.C.)
· Department of Anesthesiology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
· pubmed
This perspective critically examines the paradigm-shifting findings regarding cellular senescence's dual role in tissue biology, particularly focusing on its unexpected regenerative potential in hair growth. While cellular senescence has traditionally been viewed as a detrimental...
This perspective critically examines the paradigm-shifting findings regarding cellular senescence's dual role in tissue biology, particularly focusing on its unexpected regenerative potential in hair growth. While cellular senescence has traditionally been viewed as a detrimental process associated with aging and tissue dysfunction, research has revealed its surprising beneficial effects on tissue regeneration. We analyze the groundbreaking discovery that senescent melanocytes can stimulate hair follicle stem cells through the osteopontin-CD44 signaling pathway, challenging the conventional understanding of senescence. This perspective also evaluates the implications of this finding for both basic research and therapeutic applications, suggesting that cellular senescence represents a complex, context-dependent phenomenon rather than a uniformly detrimental process. We discuss how this new perspective necessitates a more nuanced approach to senescence-targeted therapies and opens novel therapeutic possibilities for hair loss treatment. This analysis underscores the importance of understanding senescent cell heterogeneity and their diverse functions in tissue homeostasis, which could lead to more precise therapeutic strategies in regenerative medicine.
Longevity Relevance Analysis
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Senescent melanocytes can stimulate hair follicle stem cells through the osteopontin-CD44 signaling pathway. This research challenges the traditional view of cellular senescence as solely detrimental and suggests that understanding its dual role could lead to novel therapeutic strategies in regenerative medicine, directly addressing mechanisms related to aging.
Shanshan Yao, Megan M Marron, Samaneh Farsijani ...
· Aging cell
· University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
· pubmed
Unintentional weight loss (UWL) is related to mortality and mobility limitation. Here, we aimed to develop a metabolite-based score for UWL and evaluate its prediction performance and explanation value for UWL-related health outcomes. Participants from the Health, Aging and Body ...
Unintentional weight loss (UWL) is related to mortality and mobility limitation. Here, we aimed to develop a metabolite-based score for UWL and evaluate its prediction performance and explanation value for UWL-related health outcomes. Participants from the Health, Aging and Body Composition (Health ABC) study with available metabolomics and valid follow-ups were included (N = 2286). First, in the derivation group (N = 1200), 27 of the 77 metabolites associated with incident UWL (> 3% annual UWL vs. weight stable) were selected by LASSO-logistic regression. The UWL metabolite score was calculated as a weighted sum of these 27 standardized metabolites, with higher scores indicating greater UWL risk. We then examined the standardized UWL metabolite score against all-cause mortality and incident mobility limitation using Cox regression. Overall, older adults with a one-SD higher UWL metabolite score had higher risks for mortality (1.44 [1.36, 1.52]) and mobility limitation (1.23 [1.15, 1.32]). The score also improved mortality prediction beyond traditional risk factors. Similar results were observed in the hold-out test group (n = 1086). Furthermore, this score explained 28% of the UWL-mortality relationship and 22% of the UWL-mobility limitation relationship beyond lifestyle and medical history, respectively. The score also predicted higher mortality and mobility limitation among those with intentional weight loss and weight gain, demonstrating a good Out-Of-Distribution generalizability. This metabolomic characterization of UWL is predictive of key aging outcomes in the Health ABC participants and captures a substantial portion of the mortality and mobility limitation risks related to unintentional weight loss, further validating the importance of these metabolite signatures.
Longevity Relevance Analysis
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The paper claims that a metabolite score can predict mortality and mobility limitations associated with unintentional weight loss in older adults. This research is relevant as it explores biomarkers that may help identify and mitigate risks associated with aging, contributing to a better understanding of health outcomes in the elderly population.
Barbara Arbeithuber, Kate Anthony, Bonnie Higgins ...
· Oocytes
· Department of Gynaecology, Obstetrics and Gynaecological Endocrinology, Experimental Gynaecology and Obstetrics, Johannes Kepler University Linz, Linz 4040, Austria.
· pubmed
Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo ...
Mitochondria, cellular powerhouses, harbor DNA [mitochondrial DNA (mtDNA)] inherited from the mothers. mtDNA mutations can cause diseases, yet whether they increase with age in human oocytes remains understudied. Here, using highly accurate duplex sequencing, we detected de novo mutations in single oocytes, blood, and saliva in women 20 to 42 years of age. We found that, with age, mutations increased in blood and saliva but not in oocytes. In oocytes, mutations with high allele frequencies were less prevalent in coding than noncoding regions, whereas mutations with low allele frequencies were more uniformly distributed along the mtDNA, suggesting frequency-dependent purifying selection. Thus, mtDNA in human oocytes is protected against accumulation of mutations with aging and having functional consequences. These findings are particularly timely as humans tend to reproduce later in life.
Longevity Relevance Analysis
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The paper claims that mitochondrial mutations do not increase with age in human oocytes, suggesting a protective mechanism against age-related accumulation. This research is relevant as it explores the underlying mechanisms of aging and reproductive health, which are critical for understanding longevity and the implications of delayed reproduction.
Offringa, R., Chouaref, J., Luden, T.
· plant biology
· Leiden University, Institute of Biology
· biorxiv
Members of the AT-HOOK MOTIF NUCLEAR LOCALIZED (AHL) gene family have been shown to play important roles in plant development. In Arabidopsis thaliana, one member of this family, AHL15, induces somatic embryogenesis and extends plant longevity when overexpressed - the latter thro...
Members of the AT-HOOK MOTIF NUCLEAR LOCALIZED (AHL) gene family have been shown to play important roles in plant development. In Arabidopsis thaliana, one member of this family, AHL15, induces somatic embryogenesis and extends plant longevity when overexpressed - the latter through strong repression of several ageing-related developmental transitions. However, its direct target genes and the mechanisms by which it regulates their expression have remained elusive to date. In this study we identified the genome-wide DNA binding sites of AHL15, and show that AHL15 binds throughout the genome at AT-rich sequences near the transcription start- and end sites in regions depleted of epigenetic marks. We show that induction of AHL15 activity causes strong and rapid changes in transcription, with the majority of the differentially expressed genes being downregulated but without directly affecting chromatin accessibility, resulting in developmental defects. In addition, AHL15 binding to regions near the transcription start and end sites was enhanced at genes that were differentially expressed upon AHL15 induction, and was especially strong near the transcription start site of upregulated genes and near the transcription end site of downregulated genes. Finally, we show that AHL15 shares binding sites with the chromatin architectural protein GH1-HMGA2/HON5, which was previously shown to alter transcription by disrupting gene loop formation. Together, our findings suggest that AHL15 affects the expression of its target genes by regulating the 3D organization rather than the accessibility of chromatin.
Longevity Relevance Analysis
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AHL15 extends plant longevity by binding to chromatin and regulating gene expression. The study addresses mechanisms that could influence aging processes in plants, which is relevant to understanding longevity.
Diana C Hilpert, Muhammad Abdul Haseeb, Sharon E Bickel
· Molecular biology of the cell
· Department of Biological Sciences, Dartmouth College, 78 College St. Hanover, NH 03755.
· pubmed
Meiotic segregation errors in human oocytes are the leading cause of miscarriages and trisomic pregnancies and their frequency increases exponentially for women in their thirties. One factor that contributes to increased segregation errors in aging oocytes is premature loss of si...
Meiotic segregation errors in human oocytes are the leading cause of miscarriages and trisomic pregnancies and their frequency increases exponentially for women in their thirties. One factor that contributes to increased segregation errors in aging oocytes is premature loss of sister chromatid cohesion. However, the mechanisms underlying age-dependent deterioration of cohesion are not well-defined. Autophagy, a cellular degradation process critical for cellular homeostasis, is known to decline with age in various organisms and cell types. Here we quantify basal autophagy in Drosophila oocytes and use GAL4/UAS inducible knockdown to ask whether disruption of autophagy in prophase oocytes impacts the fidelity of chromosome segregation. We find that individual knockdown of autophagy proteins in Drosophila oocytes during meiotic prophase causes a significant increase in segregation errors. In addition, Atg8a knockdown in prophase oocytes leads to premature loss of arm cohesion and missegregation of recombinant homologs during meiosis I. Using an oocyte aging paradigm that we have previously described, we show that basal autophagy decreases significantly when Drosophila oocytes undergo aging. Our data support the model that a decline in autophagy during oocyte aging contributes to premature loss of meiotic cohesion and segregation errors.
Longevity Relevance Analysis
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The paper claims that a decline in basal autophagy during oocyte aging contributes to premature loss of meiotic cohesion and segregation errors. This research is relevant as it investigates the mechanisms underlying age-related cellular processes, specifically how autophagy affects chromosome segregation in aging oocytes, which could provide insights into the root causes of reproductive aging.
Britton Scheuermann, Kathryn Nichol, Cathy Levenson ...
· The Journal of physiology
· Department of Kinesiology, Kansas State University, Manhattan, KS, USA.
· pubmed
The ageing global population is experiencing an increased prevalence of cerebrovascular diseases, such as stroke and dementia. This highlights a need for understanding the pathophysiological mechanisms of age-related cerebrovascular alterations, alongside benefits of intervention...
The ageing global population is experiencing an increased prevalence of cerebrovascular diseases, such as stroke and dementia. This highlights a need for understanding the pathophysiological mechanisms of age-related cerebrovascular alterations, alongside benefits of interventions such as physical activity. Therefore, our aims were to: (1) examine the impact of ageing and exercise training on cerebrovascular function and (2) to characterize age- and exercise training-related changes in the hippocampus transcriptome. Young and old male rats were randomized to a sedentary condition or exercise training for 10 weeks. In the first protocol, cerebral arteries were isolated to test vasomotor reactivity, quantify gene/protein expression and assess nitric oxide production. In the second protocol, anhedonia was assessed and hippocampal tissue collected for RNA-sequencing. Bioinformatic analyses (i.e. protein-protein interaction mapping) were performed. Ageing impaired endothelium-dependent vasoreactivity in the posterior communicating artery (PCoA), with a shift from endothelial nitric oxide synthase (NOS)- to neuronal NOS-mediated vasorelaxation, as well as alterations in oxidative stress production. In support, PCoA superoxide-mediated vasoreactivity and neuronal NOS-mediated production of NO decreased with age. Exercise enhanced vasodilatation in young rats, but the results suggested reduced cerebrovascular plasticity in older animals. In the second protocol, exercise training attenuated the age-related increase in anhedonia behaviour. Hippocampal RNA-sequencing revealed altered inflammatory and oxidative stress pathways with ageing that were mitigated by exercise training. Our findings underscore the complex interplay between vascular/neuronal factors in the ageing brain. Furthermore, these findings highlight the therapeutic potential of exercise in mitigating the adverse effects of ageing on cerebral health. KEY POINTS: Ageing is associated with increased risks of cerebrovascular disease and neurocognitive decline. Little is known about the underlying mechanisms involved in this process, limiting our ability to design appropriate interventions. Ageing is associated with alterations in cerebrovascular function, including possible changes in the mechanisms underlying vasomotor reactivity. Hippocampal RNA-seq revealed age-related alterations in neuronal, vascular, immune and oxidative-stress related signalling pathways. Exercise training may have mitigated many of these age-related changes, suggesting that enhancing physical activity may be a feasible means to preserve cerebral health in older individuals.
Longevity Relevance Analysis
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Exercise training mitigates age-related cerebrovascular dysfunction and depressive behavior through alterations in the hippocampal transcriptome. The study addresses underlying mechanisms of age-related changes in cerebrovascular health and suggests interventions that could enhance longevity and quality of life in older populations.
Yohei Arai, Nicholas W Chavkin, Yuka Arai ...
· Cellular Senescence
· Cardiovascular Medicine, Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
· pubmed
The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this cond...
The accumulation of senescent cells contributes to morbidity and mortality; however, common mechanisms underpinning this age-associated phenomenon remain elusive. Hematopoietic loss of the Y chromosome (LOY) is the most frequently acquired somatic mutation in males, and this condition has been associated with various age-associated diseases and reduced lifespan. Therefore, we investigated the role of hematopoietic LOY in promoting cellular senescence, focusing on kidney disease because of its well-documented connection with aging and senescence. Herein, a prospective cohort study revealed that LOY in blood is associated with an increased incidence of kidney diseases. Analyses of transcriptional signatures in human kidneys found that immune cell LOY is enriched in patients with kidney disease and associated with greater amounts of cellular senescence. In male mice reconstituted with bone marrow lacking the Y chromosome, renal dysfunction was accompanied by senescent cell accumulation in models of kidney injury and advanced age. Treatment with a senolytic agent promoted senolysis and preferentially inhibited the progression of renal dysfunction in LOY mice. Hematopoietic LOY led to up-regulation of multiple immune inhibitory receptors, and treatment with the combination of antibodies targeting PD-1 (programmed cell death protein 1) and SIRPα (signal regulatory protein α) reduced senescent cell accumulation and rescued the renal pathology conferred by hematopoietic LOY in the kidney injury model. Collectively, these data indicate that hematopoietic LOY contributes to pathological conditions by impairing the clearance of senescent cells through up-regulation of immune checkpoint proteins.
Longevity Relevance Analysis
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Hematopoietic loss of the Y chromosome impairs senescent cell clearance and contributes to renal disease. The study addresses a potential root cause of aging-related diseases by exploring the mechanisms of cellular senescence and immune checkpoint regulation, which are critical in understanding and potentially mitigating age-associated morbidity.
Fei Jiang, Takeshi Tohgasaki, Mayuko Kami ...
· Elastin
· Department of Mechanical Engineering, Graduate School of Sciences and Technology for Innovation, Yamaguchi University, Ube, Yamaguchi, 755-8611, Japan. [email protected].
· pubmed
Skin firmness and elasticity are largely determined by the dermal extracellular matrix, particularly the elastin fiber network. Age-related degradation of elastin alters its architecture, contributing to diminished skin resilience. However, the quantitative relationship between e...
Skin firmness and elasticity are largely determined by the dermal extracellular matrix, particularly the elastin fiber network. Age-related degradation of elastin alters its architecture, contributing to diminished skin resilience. However, the quantitative relationship between elastin fiber geometry and macroscopic skin firmness remains incompletely understood. In this study, we developed a novel computational framework integrating realistic 3D elastin fiber geometries-extracted from confocal microscopy images of human abdominal skin samples (Caucasian females, aged 38-78 years)-into a finite element (FE) model of the dermal matrix. The elastin networks were explicitly represented as beam elements within the FE domain. Unconfined compression simulations were conducted to evaluate skin's elastic resistance force and correlate it with quantified geometric parameters of the elastin networks. The results revealed a significant age-dependent decline in skin firmness, strongly associated with reductions in fiber diameter, fiber count, volume fraction, network connectivity (as indicated by increased fragmentation and reduced maximum cluster size), and the proportion of vertically oriented fibers. Among these, fiber count and maximum cluster size were the most important predictors of skin firmness. This study provides quantitative, mechanistic insights into how specific architectural alterations in elastin fibers directly impact the mechanical properties of aging skin. These findings emphasize the critical role of elastin network integrity and structural organization in maintaining skin function and offer a compelling rationale for therapeutic or cosmetic strategies aimed at preserving or restoring the elastin framework to maintain skin firmness.
Longevity Relevance Analysis
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The study quantitatively links age-related changes in elastin fiber architecture to declines in skin firmness. This research is relevant as it addresses the structural integrity of the dermal extracellular matrix, which is crucial for understanding the biological mechanisms of aging and potential interventions to maintain skin function.
Shiqi Hu, Zhenhua Li, Dashuai Zhu ...
· Advanced materials (Deerfield Beach, Fla.)
· Department of Biomedical Engineering, Columbia University, 3960 Broadway, New York, NY, 10032, USA.
· pubmed
Circulating extracellular vesicles (EVs) play a crucial role in mediating communication between different cell populations and organs, significantly influencing inflammation and vascular diseases. To evaluate the role of EVs in regulating senescence, small EVs isolated from umbil...
Circulating extracellular vesicles (EVs) play a crucial role in mediating communication between different cell populations and organs, significantly influencing inflammation and vascular diseases. To evaluate the role of EVs in regulating senescence, small EVs isolated from umbilical cord plasma (young sEVs, Y-sEVs) are compared with those from the plasma of elderly individuals (old sEVs, O-sEVs, >70 years old) to identify key cargo components. To investigate their effects on senescence, Y-sEVs or O-sEVs are administered to aged mice using transdermal microneedle patches, enabling sustained EV release into the circulation. Doxorubicin is administered to induce enhanced endothelial senescence in aged mice (22-24 months old). Single-cell RNA sequencing revealed that Y-sEV treatment downregulated senescence-related genes in endothelial cells decreased the proportion of activated fibroblasts in the heart, and reduced disease-associated microglia in the brain. Delivery of Y-sEVs via microneedle patches preserved endothelial cell function, and mitigated inflammation and senescence, whereas O-sEVs exacerbated endothelial dysfunction.
Longevity Relevance Analysis
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The paper claims that small extracellular vesicles from young blood can mitigate endothelial senescence in aged mice. This research addresses the underlying mechanisms of aging by exploring the potential of young sEVs to reverse age-related cellular dysfunction, which is directly relevant to longevity and age-related diseases.
Mamoru Oyabu, Tomoki Sato, Runa Kawaguchi ...
· Cell reports
· Graduate School of Life and Environmental Sciences, Kyoto Prefectural University, Kyoto 606-8522, Japan; Brain-Skeletal Muscle Connection in Aging Project Team, Geroscience Research Center, National Center for Geriatrics and Gerontology, Obu, Aichi 474-8511, Japan.
· pubmed
Muscle wasting leads to reduced activities of daily living, an increased number of care-dependent individuals, and increased mortality. However, the metabolomic adaptations underlying muscle wasting remain poorly understood. Here, by comparing physiological, genetically induced, ...
Muscle wasting leads to reduced activities of daily living, an increased number of care-dependent individuals, and increased mortality. However, the metabolomic adaptations underlying muscle wasting remain poorly understood. Here, by comparing physiological, genetically induced, pathological, and age-related muscle atrophy, we identify the metabolites modulated by muscle atrophic stimuli, which we term "atrometabolites." Integrated metabolomics reveal that dysfunctional polyamine synthesis is a common feature of muscle atrophy. Mechanistically, we identify that adenosylmethionine decarboxylase 1 (Amd1) and Amd2 are important for maintaining polyamine metabolism and that downregulation of Amd1 and Amd2 is a trigger of myotube atrophy. Using skeletal muscle-specific FoxO triple-knockout mice, we find that FoxOs are required for immobilization-induced metabolomic remodeling and identify FoxO-dependent atrometabolites. This study comprehensively elucidates the molecular basis of muscle metabolomic adaptation and provides the datasets that will lead to the discovery of mechanisms underlying tissue adaptation to maintain homeostasis.
Longevity Relevance Analysis
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The paper identifies specific metabolites and mechanisms involved in muscle atrophy, suggesting potential targets for interventions that could mitigate age-related muscle wasting. The study addresses a fundamental aspect of muscle health that is crucial for maintaining function and quality of life in aging populations.
Deng, J., Wang, Z.
· bioinformatics
· City of Hope
· biorxiv
Premature senescence is essential for tissue remodeling. Myocardial infarction (MI) induces pathological cardiac remodeling through fibroblast-driven extracellular matrix (ECM) production. The role of senescence in MI-induced remodeling process remains elusive. Here we identify a...
Premature senescence is essential for tissue remodeling. Myocardial infarction (MI) induces pathological cardiac remodeling through fibroblast-driven extracellular matrix (ECM) production. The role of senescence in MI-induced remodeling process remains elusive. Here we identify a gradual increment number of senescent cells within the ischemic heart, peaking at day 7 post- MI, in both wild-type and p16Ink4a-CreERT2-mT/mG senescence reporter mice. Lineage tracing shows that senescent cells transition to non-senescent state within 4 weeks after MI. We perform single-nucleus (sn) Multiome and fluorescence-based spatial transcriptomics analyses to profile senescent cells. We next generate a reference (query dataset) based on SPiDER- {beta}Gal/p16-EGFP positivity and map it back to the snMultiome dataset. We then deconvolute senescent cells in the integrated dataset using multiple computational algorisms. Through these approaches, we reveal that fibroblasts and its subpopulation-late myofibroblasts (MF)-constitute a major proportion of senescent cells, which functionally reduce ECM production. Importantly, ischemia-induced senescent MF show less soluble collagen production compared to TGF-{beta}1- induced non-senescent MF in vitro. At the functional level, depletion of senescent cells in vivo augments fibrosis and worsens cardiac myopathy post-MI. Our findings highlight the transient nature of senescent cells in the heart and underscore the importance of dynamic regulation of senescent cells post-MI.
Longevity Relevance Analysis
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The paper claims that senescent cells in the heart transition to a non-senescent state post-myocardial infarction and that their depletion worsens cardiac myopathy. This research is relevant as it explores the role of cellular senescence in cardiac remodeling, which is a fundamental aspect of aging and age-related diseases.
Julian, T. H., Dou, H., Duan, J. ...
· ophthalmology
· The University of Manchester
· medrxiv
The eye is a recognised source of biomarkers for cardiovascular and neurodegenerative disease risk. Here, we characterise the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integ...
The eye is a recognised source of biomarkers for cardiovascular and neurodegenerative disease risk. Here, we characterise the breadth of these associations and identify biological axes that may mediate them. Using UK Biobank data, we developed a multi-omic analysis pipeline integrating physiological, radiomic, metabolomic, and genomic information. We trained adversarial autoencoders (Ret-AAE) to represent optical coherence tomography (OCT) images and colour fundus photographs as 256-dimensional embeddings. Ret-AAE derived embeddings were associated with a range of cardiovascular and neurodegenerative diseases, including ischaemic heart disease, cerebrovascular disease, Parkinsons disease, and dementia. Examining associations across diverse omics datasets, we provide evidence linking ophthalmic imaging features to neurological and cardiovascular anatomy and function, lipid metabolism, and gene sets associated with neurodegenerative pathology. Collectively, our findings demonstrate that ophthalmic features reflect complex, multisystem biological processes, and reinforce the role of the eye as a composite indicator of systemic health.
Longevity Relevance Analysis
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The paper claims that ophthalmic imaging features can serve as indicators of cardiovascular and neurodegenerative diseases through a multi-omic analysis. This research is relevant as it explores systemic health indicators that could potentially lead to a better understanding of aging processes and age-related diseases, although it primarily focuses on associations rather than addressing root causes of aging.
Jie Luo, Ling Chen, Xiaoxian Zhang ...
· Cell proliferation
· Cord Blood Bank Centre, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
· pubmed
Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we de...
Loss of function mutations of NDUFS4 resulted in Leigh syndrome, which is a progressive neurodegenerative disease and characterized by mitochondrial oxidative stress, inflammation and aberrant mitochondrial dynamics. However, there is currently no effective treatment. Here, we demonstrate that pioglitazone significantly mitigates mitochondrial reactive oxygen species (ROS) generation, lowers cyclooxygenase-2 (COX-2) mRNA levels, and rescues aberrant mitochondrial dynamics in vitro (increasing Opa-1 expression while decreasing Drp-1 expression). Furthermore, similar effects were observed with the selective Drp-1 inhibitor mdivi-1, suggesting that inhibiting mitochondrial fission mediates the therapeutic effects of pioglitazone. Pioglitazone administration activated AMPK phosphorylation, but these effects, along with pioglitazone's ability to reverse oxidative stress, inflammation, and mitochondrial fission, were abolished by the AMPK inhibitor compound C. In vivo, pioglitazone alleviated motor dysfunction, prolonged lifespan, and promoted weight gain in Ndufs4 KO mice. This was accompanied by enhanced mitochondrial fusion and increased levels of mitochondrial complex subunits. Consistently, pioglitazone attenuated neuroinflammation and oxidative stress in vivo. Collectively, our findings indicate that pioglitazone alleviates mitochondrial oxidative stress and inflammation through an AMPK-dependent inhibition of Drp-1-mediated mitochondrial fission. Therefore, suppression of mitochondrial fission may represent a novel therapeutic strategy for Leigh syndrome (LS).
Longevity Relevance Analysis
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Pioglitazone ameliorates mitochondrial oxidative stress and inflammation in Leigh syndrome through AMPK-dependent inhibition of mitochondrial fission. The paper addresses mitochondrial dysfunction, a key factor in aging and age-related diseases, suggesting a potential therapeutic strategy that could impact longevity.
Malcolm J Jackson
· Experimental physiology
· Department of Musculoskeletal and Ageing Science, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.
· pubmed
Skeletal muscle adaptation to contractile activity is modulated by redox signalling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H
Skeletal muscle adaptation to contractile activity is modulated by redox signalling, primarily through reactive oxygen species (ROS) such as hydrogen peroxide (H
Longevity Relevance Analysis
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The paper claims that redox signalling through reactive oxygen species modulates skeletal muscle adaptations to contractile activity. This research is relevant as it explores mechanisms that could address age-related muscle weakness, which is a significant aspect of aging and longevity.
Junhao Wen
· Nature aging
· Laboratory of AI and Biomedical Science (LABS), Department of Radiology, Columbia University, New York, NY, USA. [email protected].
· pubmed
Multi-organ biological aging clocks derived from clinical phenotypes and neuroimaging data have emerged as valuable tools for studying human aging and disease. Plasma proteomics provides an additional molecular dimension to enrich these clocks. In this study, I developed 11 multi...
Multi-organ biological aging clocks derived from clinical phenotypes and neuroimaging data have emerged as valuable tools for studying human aging and disease. Plasma proteomics provides an additional molecular dimension to enrich these clocks. In this study, I developed 11 multi-organ proteome-based biological age gaps (ProtBAGs) using 2,448 plasma proteins from 43,498 participants in the UK Biobank. Here I highlight methodological and clinical considerations for developing and using these clocks, including correction for age bias, organ specificity of proteins, sample size and underlying pathologies in the training data, which can affect model generalizability and clinical interpretability. In addition, I integrated 11 ProtBAGs with previously developed nine multi-organ phenotype-based biological age gaps to investigate genetic overlap and causal associations with disease endpoints. Finally, I show that incorporating features across organs improves predictions for systemic disease categories and all-cause mortality. These analyses provide methodological and clinical insights for developing and interpreting these clocks and highlight future avenues toward a multi-organ, multi-omics biological aging clock framework.
Longevity Relevance Analysis
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The study develops multi-organ proteome-based biological age gaps to improve predictions for systemic diseases and all-cause mortality. This research is relevant as it addresses biological aging clocks, which are crucial for understanding the mechanisms of aging and their implications for longevity and age-related diseases.
Lan Zhang, Yawei Liu, Zhijuan Hua ...
· Myocytes, Cardiac
· Department of Integrated Traditional Chinese and Western Medicine, Affiliated Hospital of Hebei University, Baoding, China.
· pubmed
Cardiovascular aging is a key contributor to cardiovascular diseases (CVDs). As individuals age, the frequency and severity of cardiovascular events rise, establishing CVDs as a primary cause of death in older adults. Therefore, the development and exploration of drugs or bioacti...
Cardiovascular aging is a key contributor to cardiovascular diseases (CVDs). As individuals age, the frequency and severity of cardiovascular events rise, establishing CVDs as a primary cause of death in older adults. Therefore, the development and exploration of drugs or bioactive molecules that can effectively prevent cardiovascular aging and related diseases are urgently needed. This study evaluated the effects of salidroside, a key component of Rhodiola rosea extract, on cardiomyocyte senescence. We established an in vitro cardiomyocyte senescence model using D-gal/H
Longevity Relevance Analysis
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Salidroside activates the AMPK-mediated signaling pathway to alleviate cardiomyocyte senescence. This paper addresses a mechanism related to cardiovascular aging, which is a significant aspect of longevity research.
Yuxuan Jiang, Guo-Yang Li, Keshuai Hu ...
· Blood Pressure
· Institute of Biomechanics and Medical Engineering, AML, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China.
· pubmed
Arterial biomechanical indicators have long been recognized as fundamental contributors to the physiology and pathology of cardiovascular systems. Probing multiple biomechanical parameters of arteries simultaneously throughout the cardiac cycle is highly important but remains cha...
Arterial biomechanical indicators have long been recognized as fundamental contributors to the physiology and pathology of cardiovascular systems. Probing multiple biomechanical parameters of arteries simultaneously throughout the cardiac cycle is highly important but remains challenging. Here, we report a method to quantify arterial anisotropic stiffness, arterial wall stresses, and local blood pressure in a single measurement. With programmed ultrasound excitation and imaging, arterial axial and circumferential guided waves were simultaneously induced and measured in the longitudinal view. Then, a mechanical model was proposed to quantitatively predict the correlation of arterial guided waves with arterial biomechanical parameters. Our experimental design and biomechanical model enable an elastography method to assess temporal variations in blood pressure, bidirectional stiffness, and mechanical stresses in arterial walls. In vivo experiments were performed on healthy young, normotensive older, and hypertensive older volunteers. The results demonstrate that our method can find applications in understanding aging of cardiovascular system and diagnosis of cardiovascular diseases.
Longevity Relevance Analysis
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The paper presents a method to simultaneously measure arterial biomechanical parameters, which can enhance understanding of cardiovascular aging and disease. This research is relevant as it addresses the mechanical aspects of arterial health, which are crucial in the context of aging and longevity.
Chia-Heng Hsu, Yi-Jhan Li, Ting-Ni Guo ...
· Autophagy
· Graduate Institute of Physiology, National Taiwan University, Taipei, Taiwan.
· pubmed
Autophagic decline accompanies age and causes a deterioration in proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for macroautophagic/autophagic degradation and exocytosis. Loss of
Autophagic decline accompanies age and causes a deterioration in proteostasis, rendering neuronal demise. Rab27 functions as a vesicle regulator for macroautophagic/autophagic degradation and exocytosis. Loss of
Longevity Relevance Analysis
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Rab27 plays a crucial role in autophagic processes that may influence longevity and neuroprotection. The paper addresses mechanisms related to autophagy, which is a fundamental process in aging and longevity, suggesting potential pathways for intervention in age-related decline.
Xiaoli Li, Yuecong Chen, Zhuoyi Gao ...
· Aging cell
· National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun, China.
· pubmed
Aging is a process of gradual decline in physical and cognitive function and is a major risk factor for mortality. Despite the increasing number of relevant studies, the mechanisms regulating the aging process have not been fully elucidated. Genetic factors have long been recogni...
Aging is a process of gradual decline in physical and cognitive function and is a major risk factor for mortality. Despite the increasing number of relevant studies, the mechanisms regulating the aging process have not been fully elucidated. Genetic factors have long been recognized as key factors in controlling the rate of aging. Testes-specific protease 50 (TSP50) has been shown to be involved in the regulation of embryonic development and intestinal homeostasis, but its role in the regulation of aging remains unclear. Here, we showed that TSP50 expression was reduced in the hippocampus of both aged humans and mice. TSP50 deficiency in neural stem cells (NSCs) drove accelerated aging in mice, characterized by exacerbated age-related cognitive impairments and significantly elevated neuroinflammation. Notably, aged mice with NSCs-specific knockout of TSP50 exhibited impaired intestinal mucosal barriers, dysbiosis of gut microbiota, and a marked reduction in the production of short-chain fatty acids (SCFAs). Restoring gut microbial ecology using fecal microbiota transplantation (FMT) and overexpressing TSP50 successfully alleviated aging-associated cognitive decline and neuroinflammation. Taken together, our study suggests that TSP50 plays a critical role in the aging process and identifies gut microbiota as a pivotal mediator of TSP50's influence on age-related cognitive decline and neuroinflammation. These findings highlight the potential therapeutic value of targeting TSP50 and gut microbiota for aging, offering insights into aging mechanisms and interventions for aging-related neurodegenerative diseases.
Longevity Relevance Analysis
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TSP50 regulates aging-related cognitive decline and neuroinflammation through its influence on gut microbiota. The paper addresses mechanisms underlying aging and suggests potential therapeutic targets, aligning with the goal of understanding and intervening in the aging process.
Sanish Sathyan, Fangyu Liu, Toshiko Tanaka ...
· Aging cell
· Department of Neurology, Albert Einstein College of Medicine, Bronx, New York, USA.
· pubmed
Frailty is an age-related syndrome characterized by an increased vulnerability to adverse health outcomes in the face of stressors. By deriving a blood-based proteomic signature for frailty, the current study aimed to enhance the understanding of frailty biology and created a per...
Frailty is an age-related syndrome characterized by an increased vulnerability to adverse health outcomes in the face of stressors. By deriving a blood-based proteomic signature for frailty, the current study aimed to enhance the understanding of frailty biology and created a person-specific predictor for the risk of frailty and other adverse age-related health outcomes. A 25-protein signature (proteomic frailty index [pFI]) predictive of the cumulative frailty index (FI) in the LonGenity cohort was derived using a penalized regression method. The pFI was significantly correlated with the FI at baseline (Pearson r = 0.58) and showed significant associations with age-related chronic conditions, incident mortality, and clinical measures. In an independent cohort of 5195 participants in the Atherosclerosis Risk in Communities study, pFI was successfully validated with measured FI (r = 0.61, p < 0.001) and was associated with physical frailty at baseline (p < 0.001). The pFI was significantly associated with physical, clinical, and cognitive measures, as well as incident mortality (HR [95% CI] = 1.13 [1.12-1.14]) and dementia (HR [95% CI] = 1.07 [1.05-1.09]) after accounting for demographic factors. The pFI was further validated against FI (r = 0.45, p < 0.001) in a second independent study in 654 participants from the Baltimore Longitudinal Study of Aging. In conclusion, we identified and validated a 25-protein signature as an index of frailty that also captures overall well-being, health, and risk for key age-related diseases.
Longevity Relevance Analysis
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The paper claims to have identified a 25-protein signature that predicts frailty and associated health outcomes in older adults. This research is relevant as it seeks to enhance the understanding of frailty biology, which is a critical aspect of aging and overall health in older populations, potentially addressing root causes of age-related vulnerabilities.
Aaron O Gonzalez, Parveez A Abdul Azees, Jerry P Chen ...
· Aging cell
· Department of Comprehensive Dentistry, UT Health San Antonio, School of Dentistry, San Antonio, Texas, USA.
· pubmed
Older adults are the primary population for cell-based therapies for age-related diseases, but the efficacy of administering autologous mesenchymal stem cells (MSCs) is impaired due to biological aging. In the present study, we cultured aging adipose (AD)-derived MSCs from > 65-y...
Older adults are the primary population for cell-based therapies for age-related diseases, but the efficacy of administering autologous mesenchymal stem cells (MSCs) is impaired due to biological aging. In the present study, we cultured aging adipose (AD)-derived MSCs from > 65-year-old donors on extracellular matrix (ECM) synthesized by human amniotic fluid-derived pluripotent stem cells (ECM Plus) versus tissue culture plastic (TCP) and hypothesized that ECM Plus provided an ideal "young" microenvironment for reactivating and preserving early-stage progenitor cells within aging AD-MSCs. To test our hypothesis, we serially sub-cultured aging AD-MSCs on ECM Plus or TCP and characterized the cells both phenotypically and functionally, and then analyzed the cells at the single-cell transcriptomic level for the mechanisms that control cell fate. The results showed that the maintenance of aging AD-MSCs on ECM Plus significantly restored their quantity and quality. The mechanisms responsible for these effects were associated with a remarkable up-regulation of intracellular CD74 when cells were maintained on ECM Plus compared to TCP, which triggered activation of the phosphoinositide-3-kinase (PI3K) pathway as a key modulator of cell survival (anti-apoptosis) and suppression of cellular senescence. Moreover, AD-MSCs maintained on ECM Plus increased their expression of HLA-DR and stimulated T cell activity. These findings challenge the "immune privilege" of allogeneic MSCs as a universal source for MSC-based therapies. The present study leads to a new paradigm for treating age-related diseases: serial administration of rejuvenated autologous MSCs, which may not only replace aged MSCs but also gradually reverse the aged microenvironment.
Longevity Relevance Analysis
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The study claims that culturing aging adipose-derived mesenchymal stem cells on a young extracellular matrix can protect them from senescence and apoptosis, enhancing their potential for cell-based therapies in age-related diseases. This research addresses the biological aging of stem cells, which is a root cause of diminished efficacy in therapies aimed at age-related conditions, thus contributing to the understanding of rejuvenation strategies in the context of longevity.
Xie Mingzheng, Weng You
· Molecular and cellular biochemistry
· College of Physical Education and Sports Science, Hengyang Normal University, Hengyang, 421002, Hunan, China.
· pubmed
Age-related reductions in skeletal muscle insulin responsiveness promote metabolic dysregulation and contribute to an elevated probability of type 2 diabetes onset. The malfunction of nutrient-responsive signaling routes, specifically AMP-activated protein kinase (AMPK) and mecha...
Age-related reductions in skeletal muscle insulin responsiveness promote metabolic dysregulation and contribute to an elevated probability of type 2 diabetes onset. The malfunction of nutrient-responsive signaling routes, specifically AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR), constitutes a central component of this biological process. The integrated activity of these kinases in controlling energy dynamics, protein formation, and glucose processing is fundamental to ensure metabolic homeostasis in skeletal muscle tissue. Through its modulation of AMPK and mTOR pathways, exercise helps reinstate signaling equilibrium and supports better insulin efficacy in aging skeletal muscle. This review explores the molecular mechanisms by which different forms of exercise-endurance, resistance, and combined training-modulate the AMPK/mTOR axis in aging muscle. This analysis focuses on exercise-induced AMPK signaling as a catalyst for mitochondrial development, enhanced glucose processing, and intensified fatty acid breakdown, while also temporally coordinating mTOR activity to support muscle maintenance without exacerbating insulin resistance. By integrating insights from aging biology, exercise physiology, and molecular metabolism, this review highlights the therapeutic potential of targeting AMPK/mTOR signaling through physical activity to combat insulin resistance in the elderly.
Longevity Relevance Analysis
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Exercise modulates the AMPK/mTOR signaling axis to improve insulin sensitivity in aging muscle. This paper is relevant as it addresses the underlying mechanisms of metabolic dysregulation in aging, focusing on how exercise can counteract insulin resistance, which is a significant aspect of age-related decline in metabolic health.
Anamika Nanda, Daniel H Aslan, M Katherine Sayre ...
· GeroScience
· Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA. [email protected].
· pubmed
A physically active lifestyle benefits cellular aging, however the mechanisms linking physical activity (PA) with longevity remain unclear. PA is associated with longer telomere length (TL), while shorter TL has been associated with increased cellular aging. Some research suggest...
A physically active lifestyle benefits cellular aging, however the mechanisms linking physical activity (PA) with longevity remain unclear. PA is associated with longer telomere length (TL), while shorter TL has been associated with increased cellular aging. Some research suggests increased levels of inflammatory markers, such as C-reactive protein (CRP), are associated with telomere dysfunction. We tested the hypothesis that CRP levels mediate the association between PA and TL. Using data from the UK Biobank, we analyzed adjusted leukocyte T/S ratio (relative telomere to single gene copy), serum CRP, and moderate-to-vigorous physical activity (MVPA) data via device-measured actigraphy. We applied general linear regressions and a causal mediation analysis with 10,000 bootstraps while controlling for a range of covariates (age, BMI, smoking status, sex, ethnicity, time between data collection, time wearing the accelerometer, and the Townsend Deprivation Index). Variables of interest were transformed to approximate normality. A total of 79,873 participants were included in the final analytic sample. MVPA and CRP were both significant predictors of TL (β
Longevity Relevance Analysis
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Chronic inflammation, as mediated by CRP levels, influences the relationship between physical activity and telomere length. This paper is relevant as it explores mechanisms linking physical activity to cellular aging, specifically through telomere dynamics, which are critical in understanding longevity and age-related biological processes.
Yongwang Xue, Runting Yin, Liang Yin ...
· Food & function
· School of Pharmacy, Jiangsu University, No. 301, Xuefu Road, Zhenjiang, China. [email protected].
· pubmed
In recent years, the intensifying global aging trend has made anti-aging research a critical area of scientific interest, with dietary interventions playing an essential role. Among dietary components, food-derived microRNAs (miRNAs), emerging as biologically active nutrients, ha...
In recent years, the intensifying global aging trend has made anti-aging research a critical area of scientific interest, with dietary interventions playing an essential role. Among dietary components, food-derived microRNAs (miRNAs), emerging as biologically active nutrients, have attracted increasing attention. Accumulating evidence indicates that dietary miRNAs may exert anti-aging effects by modulating gene expression and influencing key signaling pathways related to antioxidant defense, inflammation resolution, and metabolic homeostasis. Notably, recent studies have demonstrated the potential cross-species transfer of dietary miRNAs, highlighting their biological availability and functional relevance in mammalian systems. This review systematically summarizes current advances regarding the anti-aging potential of miRNAs derived from plant-, animal- and microbe-based foods, discusses underlying molecular mechanisms, and critically evaluates their realistic potential and limitations in dietary anti-aging strategies. Finally, we highlight open questions and propose future directions to harness dietary miRNAs as viable nutritional interventions for promoting healthy aging.
Longevity Relevance Analysis
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Dietary microRNAs may exert anti-aging effects by modulating gene expression and influencing key signaling pathways. The paper is relevant as it explores potential dietary interventions that could address mechanisms of aging rather than merely treating age-related diseases.
Amir Ajoolabady, Domenico Pratico, Suhad Bahijri ...
· Cell death discovery
· National Clinical Research Center for Interventional Medicine, Shanghai, 200032, China.
· pubmed
Cellular senescence, often referred to simply as "senescence", is a complex intracellular process with diverse biological, physiological, and pathological roles. Biologically, it is essential for embryogenesis and development. Physiologically, senescence acts as a safeguard again...
Cellular senescence, often referred to simply as "senescence", is a complex intracellular process with diverse biological, physiological, and pathological roles. Biologically, it is essential for embryogenesis and development. Physiologically, senescence acts as a safeguard against tumorigenesis by preventing the proliferation of damaged or defective cells. However, persistent activation of senescence can contribute to various pathological conditions, particularly those associated with aging, cancer, and other chronic diseases such as liver and pulmonary diseases. Growing evidence links aging to heightened activation of cellular senescence, leading to the accumulation of senescent cells. Here in this perspective, we aim to decipher the latest molecular mechanisms and regulatory pathways of cellular senescence in the context of aging and aging-related diseases. Additionally, we discuss emerging research directions, highlighting current limitations and gaps in the field. Addressing these challenges may not only advance our understanding of senescence but also uncover new therapeutic opportunities.
Longevity Relevance Analysis
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The paper discusses the molecular mechanisms and regulatory pathways of cellular senescence in the context of aging and aging-related diseases. This research is relevant as it addresses the underlying biological processes associated with aging, which could lead to therapeutic opportunities for lifespan extension and the treatment of age-related conditions.
Rhine, K., Epstein, E., Carlson, N. M. ...
· cell biology
· University of California San Diego
· biorxiv
Neurodegenerative diseases are linked with dysregulation of the integrated stress response (ISR), which coordinates cellular homeostasis during and after stress events. Cellular stress can arise from several sources, but there is significant disagreement about which stress might ...
Neurodegenerative diseases are linked with dysregulation of the integrated stress response (ISR), which coordinates cellular homeostasis during and after stress events. Cellular stress can arise from several sources, but there is significant disagreement about which stress might contribute to aging and neurodegeneration. Here, we leverage directed transdifferentiation of human fibroblasts into aged neurons to determine the source of ISR activation. We demonstrate that increased accumulation of cytoplasmic double-stranded RNA (dsRNA) activates the eIF2 kinase PKR, which in turn triggers the ISR in aged neurons and leads to sequestration of dsRNA in stress granules. Aged neurons accumulate endogenous mitochondria-derived dsRNA that directly binds to PKR. This mitochondrial dsRNA leaks through damaged mitochondrial membranes and forms cytoplasmic foci in aged neurons. Finally, we demonstrate that PKR inhibition leads to the cessation of stress, resumption of cellular translation, and restoration of RNA-binding protein expression. Together, our results identify a source of RNA stress that destabilizes aged neurons and may contribute to neurodegeneration.
Longevity Relevance Analysis
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The paper claims that increased accumulation of cytoplasmic double-stranded RNA activates the integrated stress response in aged neurons, contributing to neurodegeneration. This research addresses a potential root cause of neuronal aging and neurodegeneration, which is relevant to understanding and potentially mitigating aspects of aging.
Jiayu Ye, Anupama Melam, Sheila A Stewart
· Nature reviews. Cancer
· Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA.
· pubmed
Ageing is a process characterized by a wide array of cellular and systemic changes that together increase the risk of developing cancer. While cell-autonomous mutations within incipient tumour cells are important, age-related changes in the microenvironment are critical partners ...
Ageing is a process characterized by a wide array of cellular and systemic changes that together increase the risk of developing cancer. While cell-autonomous mutations within incipient tumour cells are important, age-related changes in the microenvironment are critical partners in the transformation process and response to therapy. However, aspects of ageing that are important and the degree to which they contribute to cancer remain obscure. One of the factors that impacts ageing is increased cellular senescence but it is important to note that ageing and cellular senescence are not synonymous. We highlight open questions, including if senescent cells have phenotypically distinct impacts in aged versus young tissue, or if it is the cell type that dictates the impact of senescence on tissue homeostasis and disease. Finally, it is probable that our current definition of cellular senescence encompasses more than one mechanistically distinct cellular state; thus, we highlight phenotypic differences that have been noted across cell types and tissues of origin. This Review focuses on the role that senescent stromal cells have in cancer, with a particular emphasis on fibroblasts given the amount of work that has focused on them.
Longevity Relevance Analysis
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The paper claims that stromal senescence, particularly in fibroblasts, contributes to age-related increases in cancer risk. This research is relevant as it explores the role of cellular senescence in the aging process and its implications for cancer, addressing potential root causes of age-related diseases.
Isabelle F Foote, Jonny P Flint, Anna E Fürtjes ...
· Nature genetics
· Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA. [email protected].
· pubmed
Frailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scor...
Frailty is a multifaceted clinical state associated with accelerated aging and adverse health outcomes. Informed etiological models of frailty hold promise for producing widespread health improvements across the aging population. Frailty is currently measured using aggregate scores, which obscure etiological pathways that are only relevant to subcomponents of frailty. Here we perform a multivariate genome-wide association study of the latent genetic architecture between 30 frailty deficits, which identifies 408 genomic risk loci. Our model includes a general factor of genetic overlap across all deficits, plus six new factors indexing a shared genetic signal across specific groups of deficits. We demonstrate the added clinical and etiological value of the six factors, including predicting frailty in external datasets, highlighting divergent genetic correlations with clinically relevant outcomes and uncovering unique underlying biology linked to aging. We show that nuanced models of frailty are key to understanding its causes and how it relates to worse health.
Longevity Relevance Analysis
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The paper identifies a multivariate genetic architecture of frailty, which is linked to accelerated aging and adverse health outcomes. This research is relevant as it seeks to understand the underlying genetic factors contributing to frailty, which is a significant aspect of aging and its associated health challenges.
Jongsun Lee, Bora Lee, Hyein Lee ...
· Ribosomes
· Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Yuseong-gu, Daejeon 34141, South Korea.
· pubmed
Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here...
Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is indispensable for longevity in the nematode
Longevity Relevance Analysis
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Pelota promotes longevity and protects against age-related pathological phenotypes across species. The study addresses the role of ribosome-associated quality control in aging, focusing on a mechanism that could potentially mitigate age-related decline, thus contributing to the understanding of longevity and aging processes.
Wei Wang, Xing Zhang, Lichen Zhang ...
· ACS nano
· Department of Orthopedics, The First Affiliated Hospital of Soochow University, No. 899, Pinghai Road, Suzhou 215006, P.R. China.
· pubmed
Osteoporosis, which is characterized by reduced bone mass and structurally compromised bone tissue, along with aberrant levels of reactive oxygen species (ROS) and inflammation, has been a pressing clinical challenge. A large accumulation of ROS and pro-inflammatory factors can r...
Osteoporosis, which is characterized by reduced bone mass and structurally compromised bone tissue, along with aberrant levels of reactive oxygen species (ROS) and inflammation, has been a pressing clinical challenge. A large accumulation of ROS and pro-inflammatory factors can result in mitochondrial dysfunction and progressive cellular senescence, impeding efficacious regeneration of bone defects. Herein, in this work, a ROS-responsive hydrogel system containing HA-PBA coated Ce-ZOL nanocomposites (GHCZ) for excessive ROS scavenging and reversal of cellular senescence to accelerate bone regeneration in osteoporosis was designed and presented. The GHCZ hydrogel system allows for the sustained release of HA-PBA coated Ce-ZOL nanoparticles, which may scavenge the extracellular and intracellular ROS of BMSCs and macrophages through their prominent enzyme-like catalytic effect. Moreover, the GHCZ hydrogel system transforms the polarization phenotype of macrophages into anti-inflammation M2 type and inhibits pro-inflammatory cytokines. Meanwhile, it could reverse the senescence of BMSCs and apparently elevate their pro-osteogenic capacity through safeguarding mitochondrial function and reprograming the metabolic processes, ultimately promoting the healing of bone defects. Based on
Longevity Relevance Analysis
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The paper claims that a ROS-responsive hydrogel can reverse cellular senescence and enhance bone regeneration in osteoporosis. This research addresses the underlying mechanisms of cellular senescence and oxidative stress, which are key factors in aging and age-related diseases.
Ee Phie Tan, Nora Lyang, Saam Doroodian ...
· Caenorhabditis elegans
· Development, Aging and Regeneration Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037.
· pubmed
The degradation of cellular components through autophagy is essential for longevity and healthy aging. However, autophagy function decreases with aging, contributing to age-related diseases. In this study, we characterized a small-molecule activator of autophagy called
The degradation of cellular components through autophagy is essential for longevity and healthy aging. However, autophagy function decreases with aging, contributing to age-related diseases. In this study, we characterized a small-molecule activator of autophagy called
Longevity Relevance Analysis
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The paper claims that the small-molecule activator AA-20 enhances autophagy, improving proteostasis and potentially extending lifespan. This research addresses the decline of autophagy with aging, which is a root cause of age-related diseases, making it relevant to longevity and healthy aging.
Xin Liu, Heng Liu, Yuan Lin ...
· European heart journal
· State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology, College of Pharmacy, and Department of Cardiology, The Second Affiliated Hospital, Harbin Medical University, 157 Baojian Road, Harbin 150081, China.
· pubmed
Vascular ageing often accompanies inflammation, contributing to the onset of local or systemic vascular diseases. Nevertheless, limited research focuses on pivotal factors triggering chronic vascular inflammation and associated pathological changes. This study aimed to investigat...
Vascular ageing often accompanies inflammation, contributing to the onset of local or systemic vascular diseases. Nevertheless, limited research focuses on pivotal factors triggering chronic vascular inflammation and associated pathological changes. This study aimed to investigate the role of methyltransferase-like protein 14 (METTL14) in inflammation in the pathogenesis of vascular ageing.
Longevity Relevance Analysis
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Deletion of METTL14 reduces inflammation associated with vascular ageing. The study addresses a key factor in the mechanisms of vascular ageing, which is directly related to the biological processes of aging and potential interventions for age-related diseases.
Eunseok Kang, Rosa Haque, Hanseul Lee ...
· BMB reports
· Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 34141, Korea.
· pubmed
RNA modifications are key epigenetic alterations that play regulatory functions in RNA biology, including RNA stability and translation. Emerging evidence indicates that RNA modification is crucial for various physiological and pathological processes, including aging. This review...
RNA modifications are key epigenetic alterations that play regulatory functions in RNA biology, including RNA stability and translation. Emerging evidence indicates that RNA modification is crucial for various physiological and pathological processes, including aging. This review describes functions of key RNA modifications, including N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), 2'-O-methylation (Nm), N1-methyladenosine (m1A), adenosine-to-inosine (A-to-I) RNA editing, pseudouridylation (ψ), and N4-acetylcytidine (ac4C), highlighting their roles in aging and age-associated diseases. We also discuss dynamics of RNA modifications and associated protein factors during aging. This review provides important information on molecular mechanisms underlying aging regulation, focusing on effects of RNA modifications, which can help us understand healthy longevity in humans.
Longevity Relevance Analysis
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RNA modifications play crucial roles in aging and age-associated diseases. The paper discusses the molecular mechanisms of RNA modifications, which are directly linked to the regulation of aging processes, making it relevant to longevity research.
Laura Boose de Mendonça, Guido Lenz, Eduardo Cremonese Filippi-Chiela
· Biochemical Society transactions
· Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul 91501-970, Brazil.
· pubmed
Senescent cells (SnCs) have typical changes in multiple features, such as increased cellular and nuclear size, morphofunctional alterations in organelles, and high secretory activity. The literature generally groups cellular changes and the non-proliferative character of SnCs int...
Senescent cells (SnCs) have typical changes in multiple features, such as increased cellular and nuclear size, morphofunctional alterations in organelles, and high secretory activity. The literature generally groups cellular changes and the non-proliferative character of SnCs into the autonomous senescent phenotype. In contrast, the influence of molecules and extracellular vesicles secreted by SnCs characterizes their non-autonomous phenotype. Unlike the detailed characterization of the structure of SnCs, the discussion regarding SnC states, which are characterized by the comprehensive integration of multiple features a cell harbors in a given moment, is still incipient. This review discusses the possible SnC states (SenStates) and their influence in pathophysiological contexts. We also discuss the main mechanisms and molecular players involved in the establishment and dynamics of these states, such as transcription factors, epigenetic marks, chromatin structure, and others. Finally, we discuss the biological relevance and potential clinical applications of SenStates, as well as open questions in the field.
Longevity Relevance Analysis
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The paper discusses the various states of senescent cells and their influence on pathophysiological contexts. This research is relevant as it addresses the mechanisms underlying cellular senescence, which is a key factor in aging and age-related diseases, potentially leading to strategies for lifespan extension.
Susanne Holtze, Defne Demirtürk, Oliver Ohlenschläger ...
· Transcriptome
· Department of Reproduction Management, Leibniz Institute for Zoo and Wildlife Research, Berlin, Germany. [email protected].
· pubmed
The olm (Proteus anguinus), with a predicted maximum lifespan of more than 100 years, is the longest-lived amphibian, which in addition possesses a range of unique adaptations to its dark, subterranean cave habitat. To assess the underlying molecular signatures, we present the fi...
The olm (Proteus anguinus), with a predicted maximum lifespan of more than 100 years, is the longest-lived amphibian, which in addition possesses a range of unique adaptations to its dark, subterranean cave habitat. To assess the underlying molecular signatures, we present the first comprehensive transcriptome of the olm. Our study provides gene expression data across six organs and comparative genomics analyses, accessible via an interactive web server: http://comp-pheno.de/olm . The data uncover significant organ-specific gene expression, with the brain showing the highest number of organ-specific expressed genes. Our findings reveal significantly more genes under strong negative selection than positive selection, particularly in brain-specific expressed genes. Processes under positive selection in the olm resemble those in other long-lived species.
Longevity Relevance Analysis
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The paper claims to provide insights into the gene expression and evolutionary adaptations of the olm, particularly in relation to its longevity. The research is relevant as it explores the molecular basis of longevity in a long-lived species, potentially shedding light on mechanisms that could inform aging research.
R A Santana, J M McWhirt, G J Brewer
· GeroScience
· Department of Biomedical Engineering, University of California Irvine, Irvine, CA, 92697, USA.
· pubmed
Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less cl...
Age-related declines in neuronal bioenergetic levels may limit vesicular trafficking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer's model mice and a novel genetically encoded fluorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free GTP colocalized in the mitochondria decreased with age accompanied by the accumulation of free GTP-labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while bafilomycin inhibition of autophagy raised GTP levels. Twenty-four-hour supplementation of aged neurons with the NAD precursor nicotinamide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endocytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates, improved viability, and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy deficits that impair autophagy and endocytosis. GTP deficits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.
Longevity Relevance Analysis
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The paper claims that age-related decreases in GTP levels can be restored, leading to improved autophagy and endocytosis in neurons. This research addresses a potential root cause of age-related cellular dysfunction, specifically in the context of Alzheimer's disease, which is relevant to understanding and potentially mitigating aspects of aging.
Bene, M. R., Chung, T., Fountain, W. A. ...
· physiology
· Division of Geriatric Medicine and Gerontology, Johns Hopkins School of Medicine, Baltimore, Maryland, USA
· biorxiv
Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca2+)- and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle p...
Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. While exercise mitigates sarcopenia by transiently activating calcium (Ca2+)- and reactive oxygen species (ROS)-dependent signaling pathways that enhance muscle performance and adaptation, these same signals become chronically elevated in aged skeletal muscle and promote functional decline. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key transducer of both Ca2+ and ROS signals during exercise. Here we show that CaMKII is chronically activated in aged muscles, promoting muscle dysfunction. Muscle-specific expression of a constitutively active CaMKII construct in young mice recapitulates features of aging muscles, including impaired contractility, progressive atrophy, mitochondrial disorganization, formation of tubular aggregates, and an older transcriptional profile characterized by the activation of inflammatory and stress response pathways. Mediation analysis identified altered heme metabolism as a potential mechanism of CaMKII-induced weakness, independent of muscle atrophy. Conversely, partial inhibition of CaMKII in aged muscle improved contractile function and shifted the transcriptome toward a more youthful state without inducing hypertrophy. These findings identify chronic CaMKII activation as a driver of functional and molecular muscle aging and support the concept that CaMKII exemplifies antagonistic pleiotropy, whereby its beneficial roles in promoting muscle performance and adaptation during youth may incur deleterious consequences in aging. We propose that persistent CaMKII activation in aged skeletal muscle reflects unresolved cellular stress and promotes maladaptive remodeling. Enhancing physiological reserve capacity through exercise, in combination with temporally targeted CaMKII inhibition, may help restore adaptive CaMKII signaling dynamics and preserve muscle function in aging.
Longevity Relevance Analysis
(5)
Chronic activation of CaMKII in aged skeletal muscle drives functional decline and muscle aging. The paper addresses the underlying mechanisms of muscle aging and proposes potential interventions, making it relevant to longevity research.
Xiu Fan, Qili Qian, Wenran Li ...
· Genome research
· China National Center for Bioinformation, Beijing Institute of Genomics.
· pubmed
Epigenetic drift refers to the gradual and stochastic accumulation of epigenetic changes, such as DNA methylation variability, with advancing age. Although increasingly recognized for its potential role in aging biology, its extent, biological significance, and population specifi...
Epigenetic drift refers to the gradual and stochastic accumulation of epigenetic changes, such as DNA methylation variability, with advancing age. Although increasingly recognized for its potential role in aging biology, its extent, biological significance, and population specificity remain insufficiently characterized. Here, we present the first comprehensive epigenome-wide drift study (EWDS) in a large Chinese cohort (n = 3,538), with replication in two independent Chinese (total n = 1,467) and two European cohorts (total n = 956), to investigate the scale and relevance of epigenetic drift across populations. Through simulation, we identified White's test as the most powerful method among four alternatives for detecting age-associated methylation variability. Our EWDS revealed that 10.8% (50,385 CpGs) of sites on the 850K EPIC array exhibited epigenome-wide significant drift, with 99% showing increased interindividual variability (positive drift) and 1% showing decreased variability (negative drift). Integration with single-cell RNA-seq data demonstrated that positive drift-CpGs are associated with increased transcriptional variability and upregulation in specific cell types, while negative drift-CpGs exhibit the opposite effect. We developed epigenetic drift scores (EDSs) to quantify individual drift burden; these scores are strongly age-associated and correlate with lipidomic profiles and clinical aging indicators. Longitudinal data confirm within-individual accumulation of drift over time. Finally, a GWAS of EDS identified genetic determinants of drift magnitude, including heritable loci (e.g.,
Longevity Relevance Analysis
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The paper claims that epigenetic drift scores (EDSs) can quantify individual drift burden and are strongly associated with aging indicators. This research is relevant as it explores the underlying mechanisms of aging through epigenetic changes, potentially linking these alterations to broader implications in longevity and age-related biological processes.
Leng, H., jiang, j., Gassner, K. ...
· cell biology
· Institute for Research in Biomedicine (IRB Barcelona)
· biorxiv
Mitochondrial heteroplasmy, the co-existence of different mitochondrial genomes within a cell, is linked to aging and disease. Patients with heteroplasmy due to mitochondrial mutations experience multiple organ complications, particularly poor bone health and bone structure defec...
Mitochondrial heteroplasmy, the co-existence of different mitochondrial genomes within a cell, is linked to aging and disease. Patients with heteroplasmy due to mitochondrial mutations experience multiple organ complications, particularly poor bone health and bone structure defects. However, the mechanisms involved are generally unknown, due largely to the difficulty of manipulating mtDNA in vivo. To overcome this, we leveraged a heteroplasmic mouse model and discovered that mitochondrial heteroplasmy affects a fundamental developmental process. Specifically, the differentiation of osteoclasts, which resorb bone tissue and maintain bone homeostasis. Mechanistically, there was a reduced localization of specifically respiratory complex I subunits in mitochondria in heteroplasmic mice, disrupting ATP production and osteoclast differentiation. In addition, autophagic flux is exhausted, and the autophagy inducer spermidine restores mitochondrial health and rescues osteoclast activity, both in mice and in cells from patients with primary mitochondrial disease. Together, we identify the mechanisms by which mitochondrial heteroplasmy impacts osteoclastogenesis and discover spermidine as a modulator of this process, which presents a potential treatment for human heteroplasmic conditions such as mitochondrial diseases, which are largely untreatable.
Longevity Relevance Analysis
(5)
Mitochondrial heteroplasmy disrupts osteoclast differentiation and bone resorption by impairing respiratory complex I. The study addresses the mechanisms by which mitochondrial dysfunction contributes to aging-related bone health issues, suggesting potential therapeutic interventions that target the root causes of age-related decline.
Rajesh, A., Havas, A. P., Arnold, R. ...
· cell biology
· Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA
· biorxiv
Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in th...
Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.
Longevity Relevance Analysis
(5)
The paper claims that targeting Cyclin D1-CDK6 can reduce senescence-driven inflammation and improve physical performance in aged mice. This research addresses the mechanisms of cellular senescence and its role in aging, providing insights into potential therapeutic strategies for age-related functional decline.
Shinsuke Nirengi, Benjamin Buck, Devleena Das ...
· Calcium-Calmodulin-Dependent Protein Kinase Type 2
· Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
· pubmed
Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis o...
Aging poses significant challenges to cardiovascular health necessitating novel therapeutic approaches. This study investigates the potential of the brown adipose tissue (BAT) derived lipokine 12,13-diHOME to mitigate age-induced impairments in cardiovascular function. Analysis of human and rodent plasma signaling lipids reveals a decline in 12,13-diHOME levels with age. Transplantation of BAT or sustained upregulation of 12,13-diHOME effectively preserved cardiac function in aged male and female mice. Bulk RNA-Seq of hearts from aged mice reveals significant increases in pathways involved in ER stress and fibrosis which were partially attenuated by BAT transplantation or sustained upregulation of 12,13-diHOME. Mechanistically, in vivo and in vitro models demonstrate that 12,13-diHOME alleviated ER stress through CaMKII inhibition, particularly in males. These findings underscore 12,13-diHOME as a promising candidate for combating age-related cardiovascular dysfunction, offering insights into potential therapeutic strategies for addressing cardiovascular diseases in aging populations.
Longevity Relevance Analysis
(4)
The study claims that 12,13-diHOME can mitigate age-related declines in cardiovascular function through the attenuation of CaMKII. This research is relevant as it addresses a potential therapeutic approach to combat age-related cardiovascular dysfunction, focusing on underlying mechanisms rather than merely treating symptoms.
Ansa E Cobham, Alexander Kenzior, Pedro Morales-Sosa ...
· npj metabolic health and disease
· Stowers Institute for Medical Research, Kansas City, MO, 64110, USA. [email protected].
· pubmed
All animals age, but the rate of aging across species varies widely. The environmental pressures and molecular factors underlying this remarkable diversity in aging across species remains largely enigmatic. The Mexican tetra, Astyanax mexicanus, provides an intriguing new model t...
All animals age, but the rate of aging across species varies widely. The environmental pressures and molecular factors underlying this remarkable diversity in aging across species remains largely enigmatic. The Mexican tetra, Astyanax mexicanus, provides an intriguing new model to study how adaptation to different environments alter aging. This species exists as the river-dwelling surface fish, living in food and light rich environments, and the blind cave-adapted cavefish, thriving in dark, nutrient-limited, caves. How adaption to these extreme environments alter aging in this species remains unknown. Here, we compared aging markers between surface and cavefish populations, focusing on morphological, behavioral changes, and molecular signatures. We found aging markers were more pronounced in surface fish, but less distinct in aged cavefish. We also observed that insulin receptor mutation is limited in its impact to increase lifespan in cavefish. Instead, metabolic shifts, particularly in mitochondrial function, may contribute to cavefish's extended longevity.
Longevity Relevance Analysis
(4)
The paper claims that cave adaptation in the Mexican tetra leads to reduced aging markers and extended longevity compared to surface fish. This research is relevant as it explores the biological mechanisms underlying aging and longevity, potentially offering insights into the root causes of aging.
Wang, Y., Ding, Y., He, C. ...
· cell biology
· Shanghaitech University
· biorxiv
Ensuring the identity and optimal aging state of cell products is critical for the efficacy and safety of cell therapies. Despite rapid iterations, there remains an urgent need for robust and easy-to-implement tests to characterize cell products. Here, we present CIAdex (Cell Ide...
Ensuring the identity and optimal aging state of cell products is critical for the efficacy and safety of cell therapies. Despite rapid iterations, there remains an urgent need for robust and easy-to-implement tests to characterize cell products. Here, we present CIAdex (Cell Identification and Aging Index), an analytical framework that utilizes single-cell Fourier-transform infrared (FTIR) spectral fingerprints and machine learning to achieve precise label-free cell identity assessment and aging quantification. CIAdex employs a Feature Extraction Processor to automatically extract FTIR spectral variables corresponding to distinct cellular biomolecular features, enabling reliable distinction of lineage-, donor-, and batch-specific cell populations using linear discriminant analysis. Through application of the XGBoost algorithm, a quantitative aging index (trPDL/trPN) was further generated for tracking cellular aging dynamics along culture expansion. Notably, trPDL/trPN quantitatively represent subtle age-related shifts among different batches and drug-induced senescence or rejuvenation effects, which are unmeasurable by existing methods. Together, our work demonstrates that CIAdex, by simultaneously label-free identity verification and aging quantification of cell populations, offers a transformative approach to interpret single-cell FTIR spectral fingerprints and provides novel metrics for quality control in cell manufacturing with significant potential for optimization and assurance of cell therapies\' safety and efficacy.
Longevity Relevance Analysis
(4)
CIAdex provides a novel framework for label-free cell identity verification and aging quantification in therapeutic cell manufacturing. The paper is relevant as it addresses the aging dynamics of cell populations, which is crucial for improving the efficacy and safety of cell therapies, thereby contributing to the understanding and management of aging in therapeutic contexts.
Connolly, M. G., Fliflet, A. M., Ravi, P. ...
· neuroscience
· University of Alberta, Canada
· biorxiv
Aerobic exercise enhances cognition in part by increasing adult hippocampal neurogenesis, angiogenesis, and astrogliogenesis. Since hippocampal atrophy is a hallmark of several neurological and psychiatric conditions- including depression, PTSD, Alzheimers disease, and aging- und...
Aerobic exercise enhances cognition in part by increasing adult hippocampal neurogenesis, angiogenesis, and astrogliogenesis. Since hippocampal atrophy is a hallmark of several neurological and psychiatric conditions- including depression, PTSD, Alzheimers disease, and aging- understanding the mechanisms by which exercise increases neurogenesis has broad therapeutic relevance. One potential mechanism involves extracellular vesicles (EVs), lipid bilayer-enclosed particles released by multiple tissues during exercise that transport bioactive molecular cargo to distant organs, including the brain. In this study, we tested whether plasma-derived EVs from exercising mice (ExerVs) are sufficient to promote hippocampal neurogenesis, astrogliogenesis, and vascular density in sedentary mice. EVs were isolated from the plasma of sedentary or exercising C57BL/6J mice and injected intraperitoneally into sedentary recipients twice weekly for four weeks. To evaluate reproducibility, the study was conducted across two independent cohorts using identical procedures. ExerV-treated mice showed a significant increase in BrdU-positive cells in the granule cell layer compared to both PBS- and SedV-treated controls in both cohorts. Approximately 90% of these cells co-expressed NeuN, indicating neuronal differentiation, while 6% co-expressed S100B;, indicating astrocyte generation. No changes were observed in vascular density across groups. These findings provide initial evidence that systemically delivered exercise-derived EVs can enhance hippocampal neurogenesis and astrogliogenesis in sedentary mice. This proof-of-concept work supports further investigation into ExerVs as a potential therapeutic strategy for conditions associated with hippocampal atrophy.
Longevity Relevance Analysis
(4)
The paper claims that exercise-induced plasma-derived extracellular vesicles can enhance hippocampal neurogenesis and astrogliogenesis in sedentary mice. This research is relevant as it explores mechanisms that could potentially address hippocampal atrophy, a significant factor in aging and age-related neurological conditions.
Liming Gui, Jiajia Sun, Qin Zhong ...
· Mitophagy
· Department of Obstetrics and Gynecology, Peking University Shenzhen Hospital, Shenzhen, China. [email protected].
· pubmed
Ovarian aging profoundly impacts reproductive health and accelerates the overall aging process, yet the development of effective therapeutic strategies remains a formidable challenge. In this study, we report the rejuvenating effects of HEP14, a natural activator of protein kinas...
Ovarian aging profoundly impacts reproductive health and accelerates the overall aging process, yet the development of effective therapeutic strategies remains a formidable challenge. In this study, we report the rejuvenating effects of HEP14, a natural activator of protein kinase C (PKC) pathway, on aged ovarian function by inducing mitophagy and effectively clearing reactive oxygen species. To ensure controlled and sustained delivery of HEP14 in vivo, we develop HEP14-loaded PLGA microspheres. Transcriptomic analysis reveals a significant overlap between the transcriptional profiles of HEP14-treated aged ovaries and those of adult ovaries, suggesting molecular rejuvenation process closely associated to HEP14-induced mitophagy. Histopathological evaluations further substantiate these findings, showing that HEP14 enhances mitophagy, exhibits antioxidative properties and promotes follicular regeneration. Consequently, ovarian endocrine function in aged mice is substantially restored. Using transmission electron microscopy, confocal microscopy, and western blot analysis alongside pharmocological inhibitors and PKC-specific siRNA, in vitro studies further demonstrate the restorative effect of HEP14 on mitophagy, leading to improved mitochondrial function and subsequent alleviation of oxidative stress in senescent ovarian granulosa cells. This effect is mediated through the activation of the PKC-ERK1/2 pathway, which plays an pivotal role in the action mechanism in HEP14. These discoveries offer new therapeutic hope for ovarian aging.
Longevity Relevance Analysis
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HEP14 treatment enhances ovarian function in aged mice by promoting mitophagy and reducing oxidative stress. This study addresses the underlying mechanisms of ovarian aging, which is a significant aspect of reproductive health and overall aging processes.
Pantelis, P., Tremoulis, D. C., Evangelou, K. ...
· immunology
· Medical School, National Kapodistrian University of Athens
· biorxiv
Background: Immunotherapy has significantly improved cancer treatment. However, it is not effective in all cancer patients, rendering the need to further delineate the differences among responders and non-responders at the molecular and cellular level. Unresponsiveness to immunot...
Background: Immunotherapy has significantly improved cancer treatment. However, it is not effective in all cancer patients, rendering the need to further delineate the differences among responders and non-responders at the molecular and cellular level. Unresponsiveness to immunotherapy has been attributed to dysfunctional immune cell states such as T-cell exhaustion and anergy, whereas the contribution of cellular senescence remains elusive. Herein, we have investigated the role of immune cell senescence in the response to checkpoint inhibitors in melanomas where these immunotherapies are applied as a first line treatment. Methods: Two senescence detecting complementary approaches were utilized in a case control study we conducted. First, we implemented a senescence molecular signature we developed, termed SeneVick retrospectively in a single cell RNA-seq dataset from melanoma patients who received immunotherapy. Prior to this analysis, the signature was extensively validated in a variety of cell/tissue contexts, senescence types and species. Second, cellular senescence was assessed via an established experimental algorithmic approach in circulating immune cells of an analogous melanoma clinical cohort. Results: Melanoma patients who did not respond to immunotherapy exhibited increased cellular senescence in their CD8+ T-cells, CD4+ T-cells, B-cells and NK cells compared to responders. This phenomenon was independent of patients\' age and not an outcome of immunotherapy, in contrast to conventional anti-cancer treatments. Interestingly, alterations of cell-cell interactions among the immune sub-populations in non-responders compared to responders were identified, suggesting the involvement of immune cell senescence in defective immune responses and treatment failure. Conclusion: Overall, our findings support cellular senescence of the immune cell compartment within the TME, as a potent determinant of the response to immunotherapy and pave the way for strategies targeting immune cell senescence, as promising approaches to improve the outcome of such interventions.
Longevity Relevance Analysis
(4)
Immune cell senescence is a determinant of the response to immunotherapy in melanoma patients. The study addresses the role of cellular senescence in immune responses, which is a key aspect of aging and its impact on treatment efficacy, thus contributing to the understanding of aging-related mechanisms in cancer therapy.
Marcu, D., Sannino, D., Dornan, A. ...
· genetics
· University of Glasgow
· biorxiv
Gut microbiota exert an evolutionarily conserved influence on ageing, from invertebrates to humans. How do microbes that are physically confined to the gut lumen affect the systemic physiological process of ageing? In female Drosophila, we show that microbiota increase expression...
Gut microbiota exert an evolutionarily conserved influence on ageing, from invertebrates to humans. How do microbes that are physically confined to the gut lumen affect the systemic physiological process of ageing? In female Drosophila, we show that microbiota increase expression of the peptide hormone Tachykinin (Tk), which corresponds to reduced lifespan. Tk is required for microbiota to shorten lifespan, with knockdown rendering flies constitutively long-lived even in the presence of an intact microbiota. This lifespan extension does not come with canonical costs to fecundity or feeding, but impacts on triacylglyceride (TAG) storage suggest adaptive functions in metabolic homeostasis. In flies with defined (gnotobiotic) microbiotas, we show that we can model Tk-dependent effects of microbiota on lifespan and TAG by monoassociation with Acetobacter pomorum. These effects require Tk in the midgut, and the cognate TK receptor TkR99D in neurons, implicating a microbiota-gut-neuron relay. This relay also appears to compromise gut barrier function in aged flies, indicating roles in healthspan as well as lifespan. However, the effect of TkR99D is independent of its reported role in insulin signalling and adipokinetic hormone signalling which, respectively, are canonical regulators of lifespan and TAG metabolism, suggesting a non-canonical role for TkR99D elsewhere in the nervous system. Altogether our results implicate a microbiota-gut-neuron axis in ageing, via a specific bacterium modulating activity of a specific and evolutionarily-conserved hormone.
Longevity Relevance Analysis
(4)
The paper claims that the microbiota-gut-neuron axis influences Drosophila ageing through the modulation of the peptide hormone Tachykinin. This research is relevant as it explores the underlying mechanisms of ageing and lifespan extension, focusing on the role of gut microbiota in systemic physiological processes related to ageing.
AlOkda, A., Yadav, S., Pacis, A. ...
· developmental biology
· McGill University
· biorxiv
As aging is the primary risk factor for many chronic diseases, geroscience aims to target aging to delay age-related decline. Here, we identify Cyrene (dihydrolevoglucosenone), a sustainable, biocompatible solvent, as a novel geroprotective compound. Cyrene extends lifespan and h...
As aging is the primary risk factor for many chronic diseases, geroscience aims to target aging to delay age-related decline. Here, we identify Cyrene (dihydrolevoglucosenone), a sustainable, biocompatible solvent, as a novel geroprotective compound. Cyrene extends lifespan and healthspan in C. elegans, improving locomotor function and resistance to oxidative, thermal, osmotic, genotoxic, and proteotoxic stress. It also confers protection in neurodegenerative models of Alzheimer\'s, Parkinson\'s, and Huntington\'s disease. Cyrene is effective when delivered during development or early adulthood and requires administration before day 8 to extend longevity. Its benefits are independent of bacterial metabolism and partially independent of the FOXO transcription factor DAF-16. Importantly, Cyrene also extends lifespan and enhances oxidative stress resistance in Drosophila melanogaster, demonstrating cross-species efficacy. These findings identify Cyrene as a novel geroprotective compound that promotes longevity, resilience, and neuroprotection. Conservation across species supports future work to dissect molecular mechanisms and test its potential in mammals.
Longevity Relevance Analysis
(5)
Cyrene is identified as a novel geroprotective compound that extends lifespan and healthspan in model organisms. The study addresses the root causes of aging by exploring a compound that promotes longevity and resilience, making it relevant to the field of geroscience.
Yucel, D., Trembley, M., Ke, Q. ...
· molecular biology
· Boston Children\'s Hospital
· biorxiv
Aging is a major risk factor for cardiovascular diseases, yet the underlying molecular mechanisms remain poorly understood. In this study, we integrated physiological characterization of cardiomyocyte (CM) aging with concurrent single-nucleus RNA-seq and ATAC-seq, and reduced rep...
Aging is a major risk factor for cardiovascular diseases, yet the underlying molecular mechanisms remain poorly understood. In this study, we integrated physiological characterization of cardiomyocyte (CM) aging with concurrent single-nucleus RNA-seq and ATAC-seq, and reduced representation bisulfite sequencing to delineate the cellular and molecular landscape of CM aging in mice. Our analysis revealed significant age-associated changes in CM physiology, including hypertrophy, fibrosis, and diastolic dysfunction. We uncovered dramatic epigenetic remodeling in aged CMs, characterized by increased chromatin accessibility and altered DNA methylation patterns. Overexpression of the DNA methylase DNMT3A in young adult mouse hearts recapitulated key features of the aged heart phenotype, establishing DNA hypermethylation as a significant regulator of age-related CM function. Furthermore, ESRRG, an orphan nuclear receptor, functions as a mediator of diastolic function in the heart. Its overexpression significantly improved diastolic function and reduced expression of a non-coding RNA that is upregulated in aged CMs. These novel insights into the molecular mechanisms underlying cardiac aging identify molecular regulators involved in age-associated cardiac remodeling.
Longevity Relevance Analysis
(5)
The paper claims that DNA hypermethylation is a significant regulator of age-related cardiomyocyte function. This research is relevant as it explores the molecular mechanisms of cardiomyocyte aging, which could contribute to understanding and potentially mitigating age-related cardiovascular diseases, addressing root causes of aging rather than just symptoms.
Ting Dong, Nianyu Li, Huirui Wang ...
· Nature aging
· Department of Natural Products Chemistry, Key Lab of Chemical Biology of the Ministry of Education, Shandong University, Jinan, China. [email protected].
· pubmed
Reproductive longevity is essential for female fertility and healthy aging; however, the role of stress response, especially stress granule accumulation, in ovarian aging remains elusive and interventions are lacking. Here, we identified deleterious mutations and decreased expres...
Reproductive longevity is essential for female fertility and healthy aging; however, the role of stress response, especially stress granule accumulation, in ovarian aging remains elusive and interventions are lacking. Here, we identified deleterious mutations and decreased expression of NCOA7, a stress-response protein related to granulosa cell senescence in women with physiological and pathological ovarian aging. NCOA7 deletion accelerates oxidative stress-related cellular senescence, ovarian aging and fecundity decline in mice. Mechanistically, NCOA7 partitions into the stress granule containing G3BP1-V-ATPase and facilitates autophagic degradation of stress granules to relieve stress. Boosting granulophagy with rapamycin or lipid nanoparticle-based mRNA delivery of NCOA7 accelerates stress granule clearance, alleviating cellular senescence in human granulosa cells and delaying ovarian aging in mice. This study depicts a mechanism for ovarian resilience to stress and provides potential targets for therapeutic strategies to alleviate ovarian aging.
Longevity Relevance Analysis
(5)
NCOA7 facilitates the autophagic degradation of stress granules, mitigating ovarian aging and enhancing reproductive longevity. This study addresses a mechanism related to the aging process and proposes potential therapeutic strategies to alleviate ovarian aging, which is directly relevant to longevity research.
Wenbo Wu, Genshiro A Sunagawa, Hong Chen
· Nature metabolism
· Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, USA.
· pubmed
Torpor is a naturally occurring state of metabolic suppression that enables animals to adapt and survive extreme environmental conditions. Inspired by this adaptation, researchers have pursued synthetic torpor-an artificially induced, reversible hypometabolic state with transform...
Torpor is a naturally occurring state of metabolic suppression that enables animals to adapt and survive extreme environmental conditions. Inspired by this adaptation, researchers have pursued synthetic torpor-an artificially induced, reversible hypometabolic state with transformative medical potential. Achieving synthetic torpor has been pursued for over a hundred years, with earlier work focused on identifying drugs for systemically suppressing metabolism. Breakthroughs in 2020 identified key torpor-regulating neurons in mice, opening new opportunities for neuromodulation-based metabolic control. Synthetic torpor has been applied in animal models for various medical applications, including ischaemic protection, organ preservation, radiation protection and lifespan extension. This Perspective examines the fundamental concepts of natural torpor, advances in approaches to induce synthetic torpor and medical applications of synthetic torpor. The capability of synthetic torpor to suppress whole-body metabolism has the potential to transform medicine by offering novel strategies for medical interventions.
Longevity Relevance Analysis
(5)
Synthetic torpor can induce a reversible hypometabolic state that may extend lifespan and improve health outcomes. The paper is relevant as it explores a novel approach to metabolic regulation that could address fundamental aspects of aging and longevity.
Abbas Mohammadi, Daniel Thomas Jones, Somayeh Mohammadi ...
· Cardiology in review
· From the Department of Medicine, Valley Health System, Las Vegas, NV.
· pubmed
Telomere attrition stands as a fundamental hallmark of cardiovascular aging, driving cellular senescence and dysfunction across endothelial, cardiomyocyte, and vascular smooth muscle compartments. This review systematically examines: (1) molecular mechanisms linking telomere shor...
Telomere attrition stands as a fundamental hallmark of cardiovascular aging, driving cellular senescence and dysfunction across endothelial, cardiomyocyte, and vascular smooth muscle compartments. This review systematically examines: (1) molecular mechanisms linking telomere shortening to oxidative stress (NOX2/PRDX1 axis), epigenetic dysregulation (subtelomeric methylation, H3K9me3 loss), and mitochondrial dysfunction; (2) clinical evidence positioning leukocyte telomere length and telomere-associated proteins (eg, TRF2, POT1) as predictive biomarkers for coronary artery disease, heart failure, and hypertension; and (3) emerging therapeutic strategies ranging from telomerase activation (TA-65, GRN510) to senolytic cocktails (dasatinib + quercetin) and CRISPR (regularly interspersed short palindromic reportsclustered regularly interspaced short palindromic repeats)-based editing (6-29% efficiency in Chinese hamster ovary models). The review further addresses methodological challenges in telomere measurement (quantitative polymerase chain reaction (PCR) vs Flow-FISH standardization) and proposes an integrated risk assessment model combining leukocyte telomere length, oxidative markers (AGEs/sRAGE ratio), and epigenetic clocks. Translationally, we discuss tissue-specific delivery systems to mitigate oncogenic risks of telomerase therapies while emphasizing mitochondrial-targeted approaches for telomere stabilization. This synthesis bridges basic telomere science with clinical cardiology, offering a roadmap for personalized vascular rejuvenation strategies.
Longevity Relevance Analysis
(5)
Telomere attrition is linked to cardiovascular aging and serves as a potential target for precision medicine interventions. The paper is relevant as it addresses the molecular mechanisms of aging and proposes therapeutic strategies aimed at mitigating the root causes of age-related cardiovascular diseases.
Jodi Protasiewicz, Sarah Snider, Mousumee Khan ...
· Longevity
· Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
· pubmed
Prolonged inactivity due to medical conditions can cause chronic muscle disuse and lead to physical incapacity and poor quality of life. Here, we developed a Drosophila model of confinement inactivity (CI) to observe its effects on lifespan and muscle function. We found that, sim...
Prolonged inactivity due to medical conditions can cause chronic muscle disuse and lead to physical incapacity and poor quality of life. Here, we developed a Drosophila model of confinement inactivity (CI) to observe its effects on lifespan and muscle function. We found that, similar to mammalian models and humans, CI negatively impacted longevity and function in Drosophila. Confined flies had impaired mobility, shorter lifespan, and reduced muscle integrity compared to their freely mobile siblings. These findings establish a new, highly efficient platform for studying long term effects of chronic sedentary behavior and muscle disuse in the genetically tractable Drosophila model. In addition, we found that temporarily removing flies from CI for scheduled bouts of forced physical exercise ameliorated negative effects, in part by improving muscle homeostasis. Finally, we tested whether muscle overexpression of 3 exercise-responsive genes, dPGC-1α, dFNDC5, or dSesn, could prevent the negative impact of CI on fly aging, even without physical exercise. We previously established that overexpression of these factors phenocopies exercise effects in aging wild-type and disease model flies. We found that when overexpressed in muscle, dSesn prevented premature declines in endurance, and dFNDC5 protected speed and endurance. This new model can be used in the future for mechanistic studies to identify preventative and therapeutic targets for diseases associated with chronic inactivity.
Longevity Relevance Analysis
(4)
Prolonged inactivity negatively impacts lifespan and muscle function in Drosophila, and exercise can ameliorate these effects. The study addresses the effects of chronic inactivity on aging and muscle health, which are critical factors in longevity research.
Power, L. N., Zawrotna, N., Dinda, M. ...
· molecular biology
· University of Virginia School of Medicine
· biorxiv
Genomic instability and loss of proteostasis are two of the primary Hallmarks of Aging. Although these hallmarks are well-defined in the literature, the mechanisms that drive genomic instability and loss of proteostasis as cells age are still largely unknown. Using budding yeast ...
Genomic instability and loss of proteostasis are two of the primary Hallmarks of Aging. Although these hallmarks are well-defined in the literature, the mechanisms that drive genomic instability and loss of proteostasis as cells age are still largely unknown. Using budding yeast replicative lifespan as a model for aging in actively dividing cells, we identified nuclear proteins that were depleted in the earliest stages of aging. We found that many age-depleted proteins were involved in ribosome biogenesis, specifically in ribosome processing, or in maintenance of chromatin stability. We focused on topoisomerase I (Top1) as a novel age-depleted nuclear protein and found that its depletion in the early stages of aging was not a result of transcriptional changes or changes in protein turnover. Despite the stark depletion of Top1 in early aging, rescue of this age-dependent depletion was actually harmful to replicative lifespan. We found that Top1, when overexpressed, disrupts the stoichiometry of the RENT complex by pulling Sir2 away from the ribosomal DNA (rDNA), a phenotype which is further enhanced when the overexpressed Top1 is catalytically dead. Loss of Sir2 from the rDNA via the overexpression of catalytically dead Top1 decreases RNA Pol II silencing of a reporter gene inside or adjacent to the rDNA, consistent with the lifespan defect. Finally, we found that the catalytic activity of Top1 plays an important role in the establishment of rDNA silencing, raising the possibility that rDNA secondary structure/DNA topology is important for RNA Pol I-dependent spreading of silent chromatin across the rDNA locus.
Longevity Relevance Analysis
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The paper claims that the depletion of topoisomerase I in early aging disrupts rDNA silencing and negatively impacts replicative lifespan. This research addresses mechanisms underlying genomic instability and proteostasis loss, which are central to the aging process.
Hu, D., Wen, W., Li, H. ...
· neuroscience
· The University of Iowa
· biorxiv
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic protein localized in the endoplasmic reticulum (ER) and pivotally involved in maintaining ER homeostasis. MANF plays an important role in mitigating neurodegenerative processes. Aging, the primary risk f...
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neurotrophic protein localized in the endoplasmic reticulum (ER) and pivotally involved in maintaining ER homeostasis. MANF plays an important role in mitigating neurodegenerative processes. Aging, the primary risk factor for neurodegenerative diseases (NDDs), is associated with significant alterations in ER function. The ER, central to protein synthesis, folding, degradation and secretion (proteostasis), experiences considerable stress in NDDs, which activates the unfolded protein response (UPR). We hypothesized that MANF and UPR is crucial for maintaining proteostasis during aging, but their efficacy declines with age, therefore increasing vulnerability to NDDs. We measured MANF levels in the brain and plasma of 1-, 4-, 11-, and 22-month-old male and female mice. A progressive decline of MANF levels was observed, with the lowest levels detected in 22 months. Reduced MANF expression was found in aged mice across several brain areas, including the cerebral cortex, olfactory bulb, thalamus, hypothalamus, hippocampus, and cerebellum. There was a sex difference in MANF levels in aged mice. Aging also altered the expression of UPR and MANF interacting proteins. Using cerebellar Purkinje cell (PC)-specific MANF deficient mice, we showed that MANF deficiency impaired motor coordination in female, but not male mice. MANF deficiency weakened spatial learning and memory in both male and female mice. Male MANF deficient mice displayed increased sociability, whereas female mice exhibit social withdrawal. Taken together, MANF expression in the brain declined with age and MANF deficiency impacted neurobehaviors in the aging animal in a sex-specific manner.
Longevity Relevance Analysis
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The paper claims that age-related declines in mesencephalic astrocyte-derived neurotrophic factor (MANF) levels impair neurobehavioral functions in mice. This research is relevant as it explores the role of MANF in maintaining proteostasis during aging, which could provide insights into the underlying mechanisms of neurodegenerative diseases and aging itself.
Yanggang Hong
· European archives of psychiatry and clinical neuroscience
· The Second School of Medicine, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China. [email protected].
· pubmed
Aging is a complex process influenced by genetic, environmental, and psychiatric factors. Recent evidence suggests that epigenetic age acceleration (EAA), a biomarker of biological aging, may be linked to psychiatric disorders, yet the causal direction remains unclear. This study...
Aging is a complex process influenced by genetic, environmental, and psychiatric factors. Recent evidence suggests that epigenetic age acceleration (EAA), a biomarker of biological aging, may be linked to psychiatric disorders, yet the causal direction remains unclear. This study employed a bidirectional two-sample Mendelian randomization (MR) analysis to explore the causal relationships between EAA (IEAA, HannumAA, GrimAA, PhenoAA) and ten psychiatric disorders. Genome-wide association study (GWAS) summary statistics from large European ancestry cohorts were used, and sensitivity analyses were conducted to ensure robustness. Forward MR analysis demonstrated that PhenoAge acceleration (PhenoAA) significantly increased the risk of attention-deficit hyperactivity disorder (ADHD) (OR = 1.043, P = 0.004), suggesting that cumulative biological aging may contribute to neurodevelopmental vulnerabilities. Conversely, Hannum age acceleration (HannumAA) was associated with a protective effect against obsessive-compulsive disorder (OCD) (OR = 0.904, P = 0.004). Reverse MR analysis revealed that autism spectrum disorder (ASD) was linked to a decrease in intrinsic epigenetic age acceleration (IEAA) (OR = 0.811, P = 0.027), while major depressive disorder (MDD) significantly increased both HannumAA (OR = 1.318, P = 0.005) and IEAA (OR = 1.226, P = 0.049). These findings suggest that psychiatric conditions may both influence and be influenced by biological aging processes. This study reveals a bidirectional link between psychiatric disorders and biological aging, showing that early-life mental health conditions may accelerate epigenetic aging and increase age-related disease risk. As psychiatric disorders are recognized as aging risk factors, these findings highlight the need for research on aging-targeted interventions in psychiatric populations.
Longevity Relevance Analysis
(4)
The paper claims that there is a bidirectional relationship between epigenetic age acceleration and psychiatric disorders. This research is relevant as it explores the connections between biological aging and psychiatric conditions, suggesting that understanding these links could lead to interventions targeting aging processes in psychiatric populations.
Manuel M Gómez de Las Heras, Elisa Carrasco, Mario Pérez-Manrique ...
· Inflammation
· Tissue and Organ Homeostasis Program, Centro de Biología Molecular Severo Ochoa (CBM), Consejo Superior de Investigaciones Científicas (CSIC)-Universidad Autónoma de Madrid (UAM), Madrid, Spain.
· pubmed
Healthy aging relies on a symbiotic host-microbiota relationship. The age-associated decline of the immune system can pose a threat to this delicate equilibrium. In this work, we investigated how the functional deterioration of T cells can affect host-microbiota symbiosis and gut...
Healthy aging relies on a symbiotic host-microbiota relationship. The age-associated decline of the immune system can pose a threat to this delicate equilibrium. In this work, we investigated how the functional deterioration of T cells can affect host-microbiota symbiosis and gut barrier integrity and the implications of this deterioration for inflammaging, senescence, and health decline. Using the
Longevity Relevance Analysis
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The paper claims that CD4 T cell therapy can preserve gut barrier integrity, counteracting inflammaging and senescence. This research addresses the functional deterioration of T cells and its impact on aging, which is directly related to the root causes of aging and age-related decline.
Zhi Yu, Pin-Shi Ni, Zhuang-Zhi Wang ...
· Cell biochemistry and biophysics
· Nanjing Normal University, Nanjing, Jiangsu, China.
· pubmed
Understanding the impact of different exercise types on skeletal muscle atrophy in older adults is crucial for designing effective strategies to combat age-related muscle loss. This study explores the molecular mechanisms through which resistance exercise (RES) and endurance exer...
Understanding the impact of different exercise types on skeletal muscle atrophy in older adults is crucial for designing effective strategies to combat age-related muscle loss. This study explores the molecular mechanisms through which resistance exercise (RES) and endurance exercise (END) mitigate skeletal muscle atrophy. By examining microRNA (miRNA) expression profiles from aging skeletal muscle datasets (GSE165632) in the Gene Expression Omnibus (GEO) database, the research aims to uncover exercise-specific miRNA signatures and their associated regulatory pathways. Using the GEO2R analysis tool, researchers identified differentially expressed miRNAs (DEmiRNAs) between RES and END groups. Predicted target genes of these miRNAs were determined through a combination of miRTarBase, micro-T, and TargetScan databases. Functional enrichment analyses, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses, were performed via the DAVID database. Transcription factors were predicted using the ChEA3 database, while protein-protein interaction (PPI) networks were constructed with the STRING database to identify hub genes for further functional enrichment studies. The analysis revealed 30 differentially expressed miRNAs in the RES group and 21 in the END group. In the RES group, key pathways such as FoxO signaling, neurotrophic signaling, insulin resistance, and AMPK were regulated by miRNAs like hsa-miR-574-5p, hsa-miR-34a-5p, and hsa-miR-21-5p. These pathways promote protein synthesis and reduce myocyte apoptosis. In the END group, hub genes were linked to FoxO, TGF-β, MAPK, and cGMP-PKG signaling pathways, regulated by miRNAs such as hsa-miR-194-5p, hsa-miR-146a-5p, and hsa-miR-6831-5p, which enhance mitochondrial function and metabolic regulation. Both exercise types shared common regulatory pathways, including MAPK, TGF-β, and PI3K-Akt, which influence genes like SMAD4 and TRAF6 that are essential for myocyte survival and fibrosis suppression. This study sheds light on the unique and overlapping miRNA-driven regulatory mechanisms behind the effects of RES and END on skeletal muscle atrophy in older adults. Resistance exercise primarily boosts protein synthesis and inhibits apoptosis via pathways like AMPK and p53, while endurance exercise enhances mitochondrial function and energy metabolism through cGMP-PKG signaling. Both exercise modalities converge on critical pathways, providing a scientific basis for developing personalized exercise programs to counteract sarcopenia.
Longevity Relevance Analysis
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The paper identifies specific miRNA signatures and regulatory pathways influenced by different exercise regimens that mitigate skeletal muscle atrophy in aging. This research is relevant as it addresses the molecular mechanisms underlying age-related muscle loss, contributing to strategies aimed at combating sarcopenia, a significant aspect of aging.
Pitaksin Chitta, Timothy M Barrow, Busadee Pratumvinit ...
· Scientific reports
· Research Division, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
· pubmed
Epigenetic age provides a reliable biomarker for biological aging, reflecting the cumulative impact on health over time. Frailty is common among elderly individuals and is further compounded by hypertension, which increases the risk associated with aging. Therefore, we examined t...
Epigenetic age provides a reliable biomarker for biological aging, reflecting the cumulative impact on health over time. Frailty is common among elderly individuals and is further compounded by hypertension, which increases the risk associated with aging. Therefore, we examined the relationship between epigenetic aging and frailty in a non-Western population and explored synergistic effects of frailty and hypertension on epigenetic age. Thai women (60-80 years) were assessed for physical, blood, and biochemical parameters. Age acceleration (AA) residuals were derived to explore deviations between chronological and epigenetic age. We classified 126 participants into robust, pre-frail, and frail groups based on the Fried phenotype and Kihon Checklist. GrimAge1 and GrimAge2 outperformed other epigenetic age estimators in terms of correlation with frailty status. Furthermore, these age models were significantly correlated with physical performance tests. AA varied significantly among groups, with robust individuals having lower Grim1AA and Grim2AA levels than pre-frail individuals. Furthermore, hypertensive participants with pre-frail had significantly different levels of Grim1AA and Grim2AA compared to robust without hypertension. Our findings reveal a complex relationship among frailty, epigenetic age, physical performances, and hypertension. Grim2Age exhibits a strong correlation with chronological age and shows accelerated AA in frail individuals, particularly those with hypertension.
Longevity Relevance Analysis
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The paper claims that epigenetic aging, as measured by GrimAge models, is significantly correlated with frailty and hypertension in elderly women. This research is relevant as it explores the biological mechanisms of aging and frailty, potentially contributing to our understanding of aging processes and interventions.
bin Kashem, M. S., Varnum, S., Lazorik, O. ...
· biophysics
· Washington University in St. Louis
· biorxiv
Mitochondria are multifunctional organelles that convert the potential energy stored in nutrients and intermediary metabolites into both heat and an electro- chemical proton-motive force. However, how these outputs are synchronized in cells remains an enduring question. In this w...
Mitochondria are multifunctional organelles that convert the potential energy stored in nutrients and intermediary metabolites into both heat and an electro- chemical proton-motive force. However, how these outputs are synchronized in cells remains an enduring question. In this work, leveraging multiplexed nanodi- amond quantum sensors to monitor both changes in temperature and magnetic field fluctuations in single primary cells obtained from diverse tissues in adult mice, we identified thermomagnetic correlation profiles uncovering a regulatory feedback loop in which the cell draws upon available intracellular iron to main- tain the mitochondrial electrochemical gradient. These profiles reverse in cells derived from a mouse model of Leigh syndrome and raise the intriguing pos- sibility that primary mitochondrial diseases can be understood as disorders of thermomagnetic homeostasis.
Longevity Relevance Analysis
(4)
The paper claims that mitochondrial thermomagnetic regulation is linked to intracellular iron availability and may be disrupted in primary mitochondrial diseases. This research addresses the underlying mechanisms of mitochondrial function, which are crucial for understanding aging and age-related diseases.
Plasmalogens are natural glycerophospholipids that account for approximately 15%-20% (mol%) of human tissues' cellular membrane phospholipid composition. They play an important role in lipid membrane organization and function, including acting as endogenous antioxidants. Plasmalo...
Plasmalogens are natural glycerophospholipids that account for approximately 15%-20% (mol%) of human tissues' cellular membrane phospholipid composition. They play an important role in lipid membrane organization and function, including acting as endogenous antioxidants. Plasmalogens contain a vinyl-ether linked alkyl chain at position sn-1, characteristic of vinyl-ether lipids, and often a polyunsaturated fatty acid (PUFA) acyl chain at position sn-2 of the glycerol backbone. The role of plasmalogens in various patho-physiological processes has been revealed in recent years, including various neurological disorders associated with plasmalogen deficiency. Plasmalogen Replacement Therapy (PRT) is a therapeutic approach that aims to increase plasmalogen levels in the body and address plasmalogen deficiencies in diseases such as age-related neurodegenerative diseases, cardiovascular diseases, certain genetic peroxisomal disorders, and metabolic disorders. We provide a detailed overview of current information on the role of plasmalogens in health and disease. We summarize various strategies for regulating plasmalogen levels and highlight recent advancements in therapeutic applications. We also focus on the potential application of nanomedicine for treating disorders associated with PUFA-lipid and plasmalogen deficiencies.
Longevity Relevance Analysis
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The paper discusses the therapeutic potential of plasmalogen replacement therapy to address deficiencies associated with age-related neurodegenerative diseases and other disorders. This research is relevant as it explores a potential intervention that could target underlying mechanisms related to aging and improve healthspan.
Bruno César Feltes
· Brain
· Institute of Biosciences, Department of Biophysics, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil. [email protected].
· pubmed
The disposable soma theory (DST) posits that organisms prioritize reproductive success over long-term somatic maintenance, resulting in an inevitable decline after reproduction. However, such a basis does not fully explain the human brain's capacity to preserve metabolically cost...
The disposable soma theory (DST) posits that organisms prioritize reproductive success over long-term somatic maintenance, resulting in an inevitable decline after reproduction. However, such a basis does not fully explain the human brain's capacity to preserve metabolically costly, plastic, and cognitively essential functions well beyond the reproductive peak. This Perspective challenges the universality of DST by proposing that brain aging follows a selectively resilient trajectory, shaped by post-reproductive adaptive pressures. Rather than depicting brain aging as passive deterioration, this work reinterprets it as an active and dynamic reallocation of energy and resources under systemic decline. Molecular and biochemical adaptations, such as ketone body metabolism, nicotinamide adenine dinucleotide (NAD⁺) salvage, alternative antioxidant defenses, and persistent estrogenic sensitivity, are presented as integrated strategies that ensure the selective preservation of neuronal functions. This article offers a revised theoretical lens that emphasizes adaptation, regional prioritization, and energetic economy across the lifespan, challenging some postulates of the DST.
Longevity Relevance Analysis
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The paper claims that brain aging is an active process characterized by selective resilience rather than passive deterioration. This work is relevant as it challenges existing theories of aging and proposes mechanisms that could inform strategies for promoting longevity and cognitive health.
Enikő Kutasi, Adina Chis, Mihaela Adela Vintan ...
· Molecular neurobiology
· Department of Molecular Sciences, Medical Genetics, "Iuliu Hațieganu" University of Medicine and Pharmacy, Cluj-Napoca, Romania. [email protected].
· pubmed
Telomeres play a crucial role in safeguarding DNA integrity. With each cell division, these protective structures undergo shortening, limiting the number of divisions to prevent improper genetic material distribution in aging cells. Senescent cells accumulate in tissues and contr...
Telomeres play a crucial role in safeguarding DNA integrity. With each cell division, these protective structures undergo shortening, limiting the number of divisions to prevent improper genetic material distribution in aging cells. Senescent cells accumulate in tissues and contribute to age-related changes and decreased regeneration. Various genetic conditions are linked to premature aging and the early onset of age-related disorders. Down syndrome (DS), or chromosome 21 trisomy, is a relatively frequent aneuploidy, having an incidence of 1/1000-1/1100 newborns, and a major cause of intellectual disability. DS individuals exhibit a higher prevalence and earlier onset of age-related disorders, particularly Alzheimer's disease, due to the buildup of beta-amyloid. In DS individuals, telomere erosion occurs at an accelerated rate, caused by the overexpression of numerous genes, and it is associated with various factors, including obesity, inflammation, hormonal fluctuations, physical or emotional stress, higher levels of reactive oxygen species, and autoimmune disorders. Although telomere length in DS children is initially higher than in the general population, their telomeres experience a more rapid shortening process. Developing strategies that target molecular pathways linked to telomere erosion and telomerase activity could become a key point for the therapeutic management of DS individuals.
Longevity Relevance Analysis
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The paper claims that targeting molecular pathways linked to telomere erosion could provide therapeutic management for individuals with Down syndrome. This research is relevant as it addresses the underlying mechanisms of telomere biology and its implications for aging and age-related conditions, potentially offering insights into longevity and lifespan extension strategies.
Domenico Di Fraia, Antonio Marino, Jae Ho Lee ...
· Aging
· Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany.
· pubmed
Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish....
Aging is a major risk factor for neurodegeneration and is characterized by diverse cellular and molecular hallmarks. To understand the origin of these hallmarks, we studied the effects of aging on the transcriptome, translatome, and proteome in the brain of short-lived killifish. We identified a cascade of events in which aberrant translation pausing led to altered abundance of proteins independently of transcriptional regulation. In particular, aging caused increased ribosome stalling and widespread depletion of proteins enriched in basic amino acids. These findings uncover a potential vulnerable point in the aging brain's biology-the biogenesis of basic DNA and RNA binding proteins. This vulnerability may represent a unifying principle that connects various aging hallmarks, encompassing genome integrity, proteostasis, and the biosynthesis of macromolecules.
Longevity Relevance Analysis
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The paper claims that altered translation elongation contributes to key hallmarks of aging in the killifish brain. This research addresses fundamental biological processes related to aging and identifies potential vulnerabilities in the aging brain, which could lead to insights into the root causes of aging and age-related diseases.
Yaqing Wang, Pengyu Sun, Fuqiang Yang ...
· Aging cell
· State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
· pubmed
cTAGE5/MEA6 plays a pivotal role in COPII complex assembly, ER-to-Golgi trafficking, and secretion. However, whether cTAGE5/MEA6 is involved in other cellular functions remains unclear. Here, we show that conditional cTAGE5 knockout results in embryonic lethality during developme...
cTAGE5/MEA6 plays a pivotal role in COPII complex assembly, ER-to-Golgi trafficking, and secretion. However, whether cTAGE5/MEA6 is involved in other cellular functions remains unclear. Here, we show that conditional cTAGE5 knockout results in embryonic lethality during development and premature aging in adult mice. cTAGE5 deficiency leads to abnormal nuclear structure and disturbed cell proliferation in MEF cells. Further mechanistic studies reveal that cTAGE5 localizes not only to the ER exit sites but also to other ER structures, where it interacts with the lamin B receptor (LBR). Loss of cTAGE5 disrupts LBR's localization to the inner nuclear membrane, leading to its retention in the ER and instability. This results in abnormal nuclear (envelope) morphology and cellular senescence, likely driven by activation of the P53/P21 senescence pathway. Thus, our study uncovers cTAGE5's role in maintaining nuclear envelope integrity and highlights its function and potential mechanism in preventing cellular senescence and animal aging.
Longevity Relevance Analysis
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cTAGE5 is essential for maintaining nuclear envelope integrity and preventing cellular senescence, which is linked to aging. The study addresses a potential root cause of aging by exploring the role of cTAGE5 in nuclear structure and cellular senescence, contributing to our understanding of mechanisms that may influence longevity.
Zhou, Z., Lamanna, A., Halder, R. ...
· microbiology
· Luxembourg Centre for Systems Biomedicine, University of Luxembourg
· biorxiv
The gut microbiota both adapts to, and shapes, the metabolic state of individuals. This bidirectional relationship is mediated via circulating metabolites and gene regulatory networks and interacts with many organs, including by the gut-brain axis. Here, we have processed the cec...
The gut microbiota both adapts to, and shapes, the metabolic state of individuals. This bidirectional relationship is mediated via circulating metabolites and gene regulatory networks and interacts with many organs, including by the gut-brain axis. Here, we have processed the cecum from 232 mice from our recent aging colony across age (6-24 months), diet (chow or high fat), and genetics (43 BXD strains) and sequenced their metagenome, metatranscriptome, and cecal transcriptome. We quantify changes in over 300 species caused by interactions between diet, age, and genetic background. Traditional bioinformatics approaches linked particular microbes to observed phenotypes, while newer machine learning models based microbial clusters accurately predicted host outcomes, including individual body weight (AUC = 0.92) and chronological age (AUC = 0.84). This was further enhanced by a compact 10-feature multi-omics model, combining our microbiome data with prior liver expression data to increase chronological age AUC to 0.95. Mechanistically, integrative network analyses identified dozens of significant links between particular bacterial taxa and gene expression, such as a strong negative correlation between host Ido1 expression and short-chain fatty acid (SCFA)-producing Lachnospiraceae, indicating dietary fat can modulate host tryptophan metabolism via microbiota shifts. Moreover, as our study uses inbred mice sampled across time, we have identified signature sets of taxonomies that provide excellent predictive value for future metabolic outcomes driven by metabolic networks connecting the microbiome to the host organism\'s tissues (here, cecum and liver from the same mice). By better understanding the gut-liver axis, we can understand the cellular etiologies of metabolic disease and identify earlier, personalized diagnostic biomarkers attuned to the genetic background and environmental state of the individual.
Longevity Relevance Analysis
(5)
The study identifies significant interactions between the gut microbiome and host metabolic states, suggesting potential pathways for understanding and addressing metabolic diseases related to aging. This research is relevant as it explores the gut-liver axis and its implications for metabolic health, which are crucial for understanding the biological mechanisms of aging and developing interventions that could influence longevity.
Sugai, A., Moridono, H., Bilgic, M. ...
· neuroscience
· Institute for Quantitative Biosciences, The University of Tokyo
· biorxiv
Microglial senescence contributes to inflammation and various neurodegenerative diseases. Recent single-cell transcriptome data have revealed age-associated microglial substates (AAMs) and their potential roles in the development of neurodegenerative diseases. However, the charac...
Microglial senescence contributes to inflammation and various neurodegenerative diseases. Recent single-cell transcriptome data have revealed age-associated microglial substates (AAMs) and their potential roles in the development of neurodegenerative diseases. However, the characteristics identified in each study are not necessarily consistent. Here, we perform an integrative analysis of seven previously reported single-cell RNA-seq and four single-nucleus RNA-seq datasets of microglia from young and aged mouse brains. We identify four common AAMs across all datasets and two dataset-specific AAMs. Each AAM exhibits distinct transcriptomic patterns, including alterations in ribosomal genes, Apoe, cytokine genes, interferon-responsive genes, and phagocytosis-related genes. Time-series and pseudotime analyses indicate that the production of AAMs is initiated by the upregulation of ribosomal genes. Predictions based on single-cell transcriptomic data of age-associated manipulations reveal an increase in specific AAMs in a stimulation-type-dependent manner. We also identify similar AAMs in human brains. Altogether, our large-scale integrative analysis highlights promising age-associated microglial populations, which may serve as novel therapeutic targets for age-related neurodegenerative diseases.
Longevity Relevance Analysis
(4)
The paper identifies age-associated microglial populations that may serve as novel therapeutic targets for age-related neurodegenerative diseases. The research addresses the underlying mechanisms of microglial senescence and its implications for aging and neurodegeneration, contributing to the understanding of root causes of age-related conditions.
Jingjing Huang, Maria Jose Gacha-Garay, Yu Wang ...
· Aging cell
· Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
· pubmed
Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens d...
Idiopathic pulmonary fibrosis (IPF) is a prevalent and deadly age-related disease characterized by chronic, progressive, and irreversible fibrosis. A key effector cell population in the fibroproliferative response is the fibroblasts. Fibroblast cell senescence gradually worsens during aging, and the acquisition of a senescence-associated secretory phenotype (SASP) turns senescent fibroblasts into pro-inflammatory cells. However, the mechanism promoting senescence in IPF, especially at the post-transcriptional level, is poorly understood. We recently discovered that Nudix Hydrolase 21 (NUDT21, also named CFIm25), an RNA-binding protein, plays a critical role in regulating the expression of SASP factors through alternative polyadenylation (APA). APA allows adding poly(A) tail at different sites of 3' UTR and generates transcript isoforms with different 3' UTR lengths. We found that NUDT21 was downregulated in aging and fibrotic lungs, particularly at the fibrotic foci of IPF lungs known to have abundant senescent myofibroblasts and collagens. NUDT21 knockdown in normal lung fibroblasts promoted the 3' UTR shortening of several STAT3 signaling components and enhanced STAT3 phosphorylation and the expression of several SASPs, including interleukins, collagens, and matrix metalloproteinases (MMPs). Moreover, NUDT21 downregulation may be associated with increased fibroblast senescence and abnormal mitochondrial function. Importantly, mice with Nudt21 deletion in Col1a1 expressing cells aggravated bleomycin-induced pulmonary fibrosis. Taking together, our study demonstrated an important role of NUDT21-mediated APA in regulating SASP expression and fibroblast senescence that could contribute to the pathogenesis of IPF.
Longevity Relevance Analysis
(4)
NUDT21-mediated alternative polyadenylation regulates SASP expression and fibroblast senescence in pulmonary fibrosis. This paper addresses a mechanism related to cellular senescence, which is a key aspect of aging and age-related diseases, thus contributing to the understanding of the root causes of aging.
Matlack, J. K., Miner, R. E., Lokhandwala, J. ...
· biochemistry
· Moffitt Cancer Center
· biorxiv
Protein glycation is a detrimental byproduct of living cells\' reliance on carbohydrate metabolism, and nearly all organisms encode kinases that facilitate the removal of early glycation products. In humans, these repair functions are performed by Fructosamine-3 kinase (FN3K) and...
Protein glycation is a detrimental byproduct of living cells\' reliance on carbohydrate metabolism, and nearly all organisms encode kinases that facilitate the removal of early glycation products. In humans, these repair functions are performed by Fructosamine-3 kinase (FN3K) and Ketosamine-3 kinase (KT3K) enzymes which share conserved catalytic mechanisms but differ in substrate specificity. Recent structural studies defined key active site residues required for FN3K activity on a model substrate, yet the molecular basis for differential substrate recognition by FN3K and KT3K remains unresolved. Here, we integrate phylogenetic analysis, ancestral protein reconstruction (APR), and mutational biochemistry to to elucidate how substrate specificity evolved within the fructosamine-3 kinase family. We show that conserved substrate-binding residues are required for the phosphorylation of both fructosamines and ketosamines, but do not contribute to substrate specificity. Using APR, we resurrected four ancestral fructosamine kinases that recapitulate the distinct substrate preferences of FN3K and KT3K despite differing by only 12 amino acids. Through mutational studies and structural analysis, we show that substrate specificity is modulated by an evolutionarily tuned allosteric network that enables long-range intramolecular communication. These insights provide a new mechanistic framework for understanding FN3K substrate selection and open avenues for rational design of FN3K-selective therapeutics targeting protein glycation in metabolic disease and aging.
Longevity Relevance Analysis
(4)
The paper claims that substrate specificity in FN3K is modulated by an evolutionarily tuned allosteric network. This research is relevant as it explores the mechanisms underlying protein glycation, which is implicated in metabolic diseases and aging, potentially offering insights into therapeutic strategies that could address root causes of age-related conditions.
Jacob-Dolan, J. W., Sterling, A. C., Brutus, M. E. ...
· biochemistry
· Tufts University
· biorxiv
Glycation crosslinks account for more than 40% of all known advanced glycation end products (AGEs) and are correlated with many age-related diseases. Despite much interest, crosslinking AGEs (xl-AGEs) remain poorly understood, as they have been challenging to discover, prepare, a...
Glycation crosslinks account for more than 40% of all known advanced glycation end products (AGEs) and are correlated with many age-related diseases. Despite much interest, crosslinking AGEs (xl-AGEs) remain poorly understood, as they have been challenging to discover, prepare, and quantify. Here we describe a peptide platform that is ideally suited for the study of xl-AGEs, which not only facilitates direct comparisons between the prevalence of known xl-AGEs and other AGEs, but also enables the discovery of previously unknown xl-AGEs. In this study, we use this platform to discover the first known Arg-Arg xl-AGEs, a pair of methylglyoxal-derived dihydroxyimidazolidine hemiacetal crosslink, or MIDAL, isomers. We show that MIDAL can become the major AGE, exceeding levels of all other AGEs, for substrates in which two Arg glycation sites are optimally positioned. We further demonstrate that MIDAL is readily and reversibly generated in biocompatible conditions, persisting with a half-life of more than three days. We also demonstrate that MIDAL can form in living mammalian cells, suggesting that it has the potential to be a dynamic, physiologically relevant and functional xl-AGE. This work therefore offers important insights about MIDAL formation and describes a versatile platform to enable the study of xl-AGEs under a variety of conditions. We expect that it will be highly useful for further discovery of biologically relevant glycation crosslinks that are yet to be identified.
Longevity Relevance Analysis
(4)
The paper claims to have discovered a new class of glycation-derived crosslinks (xl-AGEs) that may play a significant role in age-related diseases. The research is relevant as it addresses the formation of advanced glycation end products, which are implicated in the aging process and age-related pathologies, potentially offering insights into the underlying mechanisms of aging.
Jin, X., Tang, W., Zheng, Z. ...
· neuroscience
· Institute of Psychology, Chinese Academy of Sciences
· biorxiv
Non-pharmacological interventions (NPIs) in aging neuroscience have largely focused on intervention-specific regional effects, with limited understanding of generalizable network-level mechanisms. Here, adopting a previously unexplored gradient-based perspective of functional bra...
Non-pharmacological interventions (NPIs) in aging neuroscience have largely focused on intervention-specific regional effects, with limited understanding of generalizable network-level mechanisms. Here, adopting a previously unexplored gradient-based perspective of functional brain organization, we analyzed an NPI dataset involving four interventions in older adults (training/control group: n = 112/59). NPIs led to strengthened intra-network functional integration and maintained macroscale gradient architecture. Virtual lesion analyses identified the dorsal attention network (DAN) as a key contributor to gradient maintenance. Critically, enhanced post-intervention DAN connectivity was associated with maintained gradient structure and improved global cognition. These findings establish a unifying framework in which the DAN acts as a convergent hub through which diverse NPIs preserve functional brain organization and attenuate cognitive aging.
Longevity Relevance Analysis
(4)
The paper claims that the dorsal attention network (DAN) serves as a convergent hub through which diverse non-pharmacological interventions can preserve functional brain organization and cognitive function in aging. This research is relevant as it explores mechanisms that may help mitigate cognitive decline associated with aging, addressing a fundamental aspect of longevity and cognitive health.
Cong Chen, Tong-Yao Gao, Hua-Wei Yi ...
· Proteasome Endopeptidase Complex
· Department of Pharmacology, Zhejiang University School of Medicine, Hangzhou, China.
· pubmed
Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic lin...
Ubiquitin (Ub), a central regulator of protein turnover, can be phosphorylated by PINK1 (PTEN-induced putative kinase 1) to generate S65-phosphorylated ubiquitin (pUb). Elevated pUb levels have been observed in aged human brains and in Parkinson's disease, but the mechanistic link between pUb elevation and neurodegeneration remains unclear. Here, we demonstrate that pUb elevation is a common feature under neurodegenerative conditions, including Alzheimer's disease, aging, and ischemic injury. We show that impaired proteasomal activity leads to the accumulation of sPINK1, the cytosolic form of PINK1 that is normally proteasome-degraded rapidly. This accumulation increases ubiquitin phosphorylation, which then inhibits ubiquitin-dependent proteasomal activity by interfering with both ubiquitin chain elongation and proteasome-substrate interactions. Specific expression of sPINK1 in mouse hippocampal neurons induced progressive pUb accumulation, accompanied by protein aggregation, proteostasis disruption, neuronal injury, neuroinflammation, and cognitive decline. Conversely, Pink1 knockout mitigated protein aggregation in both mouse brains and HEK293 cells. Furthermore, the detrimental effects of sPINK1 could be counteracted by co-expressing Ub/S65A phospho-null mutant but exacerbated by over-expressing Ub/S65E phospho-mimic mutant. Together, these findings reveal that pUb elevation, triggered by reduced proteasomal activity, inhibits proteasomal activity and forms a feedforward loop that drives progressive neurodegeneration.
Longevity Relevance Analysis
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Elevated ubiquitin phosphorylation by PINK1 contributes to proteasomal impairment and promotes neurodegeneration. The paper addresses a mechanistic link between proteasomal dysfunction and neurodegeneration, which is relevant to understanding the biological processes underlying aging and age-related diseases.
Ebenebe, O. V., Kabir, R., Booher, A. ...
· physiology
· Johns Hopkins University
· biorxiv
S-nitrosoglutathione reductase (GSNOR), a regulator of protein S-nitrosylation (SNO), has been proposed as a longevity protein. GSNOR signaling has been implicated in both the alleviation and exacerbation of aging. In the context of ischemia reperfusion injury, we previously show...
S-nitrosoglutathione reductase (GSNOR), a regulator of protein S-nitrosylation (SNO), has been proposed as a longevity protein. GSNOR signaling has been implicated in both the alleviation and exacerbation of aging. In the context of ischemia reperfusion injury, we previously showed a sex-dependent response to GSNOR inhibition; cardiac damage was alleviated in males and exacerbated in females. Considering sex differences in the incidence of cardiovascular disease with age, we investigated the effect of GSNOR deletion (-/-) on age-related changes in cardiac function. We performed longitudinal 2D-echocardiography measurements in M-Mode on male and female, wildtype (WT) and GSNOR-/- mice at young (3-4 months), middle (13-15 months) and old age (18-20 months). Left ventricular wall thickness and ejection fraction decreased with age in WT mice but was maintained in GSNOR-/-. Western blot and GSNOR-activity assay showed GSNOR activity and expression decreased with age in WT females alone. Isolated cardiomyocyte force-coupling analysis showed increasing age was inversely correlated with sarcomere shortening and Ca2+ release kinetics in WT males, but not GSNOR-/-. WT females showed slower Ca2+ re-uptake after contraction and time to peak sarcomere shortening, but all other parameters were maintained. GSNOR-/- females exhibited slower Ca2+ re-uptake and decreased sarcomere shortening. Proteomic analysis of SNO from females showed upregulation of Pyruvate Dehydrogenase, E1 Beta and Dihydrolipoamide dehydrogenase in young WT females relative to middle-age mice. Together our data suggest that GSNOR deletion is cardioprotective by maintaining cardiac function in males; while in females the absence of GSNOR removes an age-essential SNO-imbalance, which may exacerbate pathologies.
Longevity Relevance Analysis
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GSNOR deletion maintains cardiac function in aging male mice while exacerbating dysfunction in females. The study investigates the role of GSNOR in age-related cardiac function, addressing potential mechanisms of aging and sex differences in cardiovascular health, which are critical for understanding longevity.
Cécile Marcourt, Claudio Rivera, Jürgen Tuvikene ...
· GeroScience
· Aix Marseille Univ, INSERM, INMED, Marseille, France.
· pubmed
Aging is associated with metabolic decline in the brain, increasing susceptibility to neurodegenerative diseases. While exercise is a well-established strategy to counteract these changes, no study has directly compared the effects of moderate-intensity continuous training (MICT)...
Aging is associated with metabolic decline in the brain, increasing susceptibility to neurodegenerative diseases. While exercise is a well-established strategy to counteract these changes, no study has directly compared the effects of moderate-intensity continuous training (MICT) and high-intensity interval training (HIIT) on cortical and hippocampal energy metabolism-key regulators of brain plasticity in aging. To address this gap, we investigated how 4-week MICT and HIIT protocols, structured according to the lactate threshold, affect endurance performance and brain metabolic markers in older Wistar rats. Both training modalities improved endurance, with HIIT demonstrating superior gains in maximal performance. However, molecular analyses revealed that MICT induced more extensive metabolic and angiogenic adaptations in the cortex and hippocampus, including the upregulation of key regulators of energy metabolism and vascularization. RNA sequencing confirmed broader transcriptomic changes following MICT, implicating pathways associated with neurogenesis, metabolic homeostasis, and cellular plasticity. While HIIT provided a time-efficient means of improving cardiovascular endurance and mitochondrial activity through different molecular pathways when compared to MICT, its impact on brain metabolism was more limited. These findings suggest that MICT is the preferred regimen for enhancing cerebral metabolic function and neurovascular adaptation, while HIIT serves as a complementary strategy to involve other brain metabolism-associated pathways and maximize aerobic fitness. A direct comparison of these modalities, as presented here, is essential for refining exercise prescriptions to support brain health in aging.
Longevity Relevance Analysis
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Moderate-intensity continuous training (MICT) induces more extensive metabolic and angiogenic adaptations in the brain compared to high-intensity interval training (HIIT) in older rats. The study addresses the effects of exercise on brain metabolism, which is crucial for understanding interventions that could mitigate age-related metabolic decline and support brain health in aging.
Battaglia, M. C., Bhalla, M., Marzullo, B. ...
· immunology
· Department of Microbiology and Immunology, University at Buffalo, Jacobs School of Medicine and Biomedical Sciences, Buffalo NY
· biorxiv
Aging drives increased susceptibility to respiratory infections by Streptococcus pneumoniae (pneumococci). Polymorphonuclear leukocytes (PMNs) are among the first responders in the lung following pneumococcal infection and are required for bacterial clearance. However, PMN antimi...
Aging drives increased susceptibility to respiratory infections by Streptococcus pneumoniae (pneumococci). Polymorphonuclear leukocytes (PMNs) are among the first responders in the lung following pneumococcal infection and are required for bacterial clearance. However, PMN antimicrobial function declines with age. To identify mechanisms underlying this decline, we performed RNA sequencing on PMNs in the lungs of young and old mice following pulmonary infection with S. pneumoniae. We observed significant transcriptomic differences across host age. Transcriptional analysis followed by functional validation revealed that in infected mice, PMNs from aged hosts failed to upregulate several effector activities including glycolysis and subsequent mitochondrial reactive oxygen species (ROS) production, which are necessary for bacterial killing by PMNs. Analysis of potential transcription factors controlling these changes indicated differential regulation by E2f2 in aged mice, which was linked to lower PMN differentiation resulting in more immature PMNs in the lungs of aged mice compared to young controls. Conversely, PMNs in aged mice displayed a higher senescence-associated secretory phenotype (SASP) score and upregulated pathways involved in cellular senescence. Follow-up functional characterization found that in uninfected hosts, PMNs in aged mice expressed higher levels of SASP factors IL-10, TNF-a, and ROS, had lower incidence of apoptosis, and had a higher proportion of cells positive for senescence-associated b-galactosidase, features of a senescent-like phenotype. In conclusion, host aging is associated with altered PMN phenotypes, including a shift toward senescent-like energy-deficient cells, which may contribute to impaired host defense and represent potential targets for improved interventions against infection in older adults.
Longevity Relevance Analysis
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Host aging induces a senescent-like phenotype in neutrophils, contributing to impaired immune responses to infections. The study addresses mechanisms of immune decline due to aging, which is directly related to understanding and potentially mitigating age-related functional deterioration.
Sturgis, J., Jiang, K., Hagstrom, S. ...
· cell biology
· Cleveland Clinic Foundation
· biorxiv
Retinal degenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and glaucoma, have been linked to mitochondrial dysfunction. However, the impact of mitochondrial DNA (mtDNA) mutation accumulation in the context of these retinopathies has yet t...
Retinal degenerative diseases, such as age-related macular degeneration (AMD), retinitis pigmentosa, and glaucoma, have been linked to mitochondrial dysfunction. However, the impact of mitochondrial DNA (mtDNA) mutation accumulation in the context of these retinopathies has yet to be thoroughly explored. Our previous studies focused on the retinal phenotype observed in the PolgD257A mutator mice (D257A), revealing the effects of aging and mtDNA mutation accumulation in the retina. We have reported that this model exhibited significant morphological and functional deficits in the retina by 6 months of age, with notable alterations in the retinal pigment epithelium (RPE) occurring as early as 3 months, including changes in the cristae density and reduction in length of mitochondria. This study investigated how mtDNA mutations affect the metabolic interaction between the retina and RPE in young (3 months) and old (12 months) wild-type (WT) and D257A mice. We assessed cellular energy production using freshly dissected retina samples from both groups through Seahorse analysis, immunofluorescence, and Western blot experiments. The analysis of aged D257A retina punches revealed significantly reduced basal and maximal mitochondrial respiration, along with increased mitochondrial reserve capacity compared to WT. However, glycolytic flux, measured as a function of extracellular acidification rate (ECAR), did not differ between WT and D257A mice. Both D257A retina and RPE exhibited decreased expression of essential electron transport proteins involved in oxidative phosphorylation. Additionally, we observed a reduction in the expression of glucose transporter 1 (GLUT-1) and lactate transporter (MCT1) at the apical surface of the RPE. Enzymes associated with glycolysis, including hexokinase II and lactate dehydrogenase A, were significantly lower in the aged D257A retina, while hexokinase I and pyruvate kinase 2 were upregulated in the RPE. These findings indicate that the accumulation of mtDNA mutations leads to impaired metabolism in both the retina and RPE. Furthermore, it suggests that glucose from the choroidal blood supply is being utilized by the RPE rather than transported to the neural retina. Mitochondrial dysfunction in RPE promotes a glycolytic state in these cells, leading to reduced availability of metabolites and, consequently, diminished overall retinal function. These results are essential for advancing our understanding of the mechanisms underlying retinal degeneration and provide a new perspective on the role of mtDNA mutations in these diseases.
Longevity Relevance Analysis
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The accumulation of mitochondrial DNA mutations impairs metabolic function in the retina and retinal pigment epithelium, contributing to retinal degeneration. This paper is relevant as it explores the underlying mechanisms of mitochondrial dysfunction, which is a significant factor in aging and age-related diseases, potentially offering insights into the root causes of retinal degeneration.
Xiao Lu, Jiao Wu, Ewud Agborbesong ...
· Cell death discovery
· Department of Internal Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
· pubmed
Diabetic kidney disease (DKD) is characterized by kidney damage and abnormal renal energy metabolism, but the molecular mechanism of DKD is still unclear. In this study, we show that p16- positive senescent cells are an important regulator in the progression of DKD. The expressio...
Diabetic kidney disease (DKD) is characterized by kidney damage and abnormal renal energy metabolism, but the molecular mechanism of DKD is still unclear. In this study, we show that p16- positive senescent cells are an important regulator in the progression of DKD. The expression of p16 and senescence are increased in the kidneys of DM mice and DKD patients. To better understand the role of p16 in DKD, we induce type 1 diabetes in INK-ATTAC mice, a mouse model that allows the selective ablation of p16-expressing cells upon administration of the drug AP20187. We found that clearance of p16-positive cells, most of them are senescent cells, (1) decreased senescence and the expression of the components of the senescence-associated secretory phenotypes (SASPs), (2) restored kidney adenosine triphosphate (ATP) content, (3) decreased the expression of the key glycolytic genes to improve the metabolic reprogramming, (4) normalized the mitochondrial metabolism through AMPK and mTOR pathway, resulting in an amelioration of the progression of DKD. In addition, p16 mediated the blocking of the cell cycle is through the CDK4-Rb pathway in DKD kidneys. This study suggests that pharmacological deletion of p16-positive senescent cells may be a novel therapeutic strategy for DKD treatment.
Longevity Relevance Analysis
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The paper claims that the clearance of p16-positive senescent cells can ameliorate the progression of diabetic kidney disease (DKD) through metabolic reprogramming. This research is relevant as it addresses the role of cellular senescence in age-related diseases, suggesting a potential therapeutic strategy that targets the underlying mechanisms of aging rather than merely treating symptoms.
Donghoon Kang, Yeji Lim, Dabin Ahn ...
· Journal of medicinal chemistry
· Department of Chemistry, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea.
· pubmed
Cellular senescence, marked by irreversible cell cycle arrest and senescence-associated secretory phenotype, contributes to aging and cancer recurrence. While chemotherapy can induce senescence in cancer cells, these therapy-induced senescent cells often resist apoptosis and prom...
Cellular senescence, marked by irreversible cell cycle arrest and senescence-associated secretory phenotype, contributes to aging and cancer recurrence. While chemotherapy can induce senescence in cancer cells, these therapy-induced senescent cells often resist apoptosis and promote tumor recurrence. The nuclear interaction between FOXO4 and p53 is crucial for senescent cell survival. Using NMR spectroscopy, we identified that hydrophobic interactions in the p53 transactivation domain play a key role in FOXO4 forkhead domain binding. Based on this structural information, we designed an optimized peptide inhibitor with reduced negative charges and incorporated a cationic cell-penetrating peptide for enhanced cellular delivery (CPP-CAND). CPP-CAND exhibited high selectivity for senescent cells, effectively disrupting nuclear FOXO4-p53 foci and inducing caspase-dependent apoptosis. Notably, it showed cytotoxicity against senescent cancer cells induced by different chemotherapeutic agents including doxorubicin and cisplatin. With its enhanced selectivity, l-amino acid composition, and shorter length, CPP-CAND represents a promising therapeutic candidate for targeting therapy-induced senescent cancer cells.
Longevity Relevance Analysis
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The paper claims that the peptide inhibitor CPP-CAND can selectively induce apoptosis in therapy-induced senescent cancer cells by disrupting FOXO4-p53 interactions. This research is relevant as it addresses the issue of cellular senescence, which is a contributing factor to aging and age-related diseases, particularly in the context of cancer recurrence.
Joruiz, S. M., Lissa, D., von Muhlinen, N. ...
· cell biology
· Center for Cancer Research, National Cancer Institute, National Institutes of Health
· biorxiv
Background: Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, ...
Background: Patients with Hutchinson-Gilford progeria syndrome (HGPS) show accelerated aging phenotypes and have shortened lifespan, with implications in physiological aging processes as well. While therapeutic approaches targeting the disease-causing abnormal protein, progerin, have been developed, further efforts to explore mechanistically distinct and complementary strategies are still critical to better treatment regimens. We previously showed that lentiviral vector-driven expression of {Delta}133p53, a natural inhibitory isoform of p53, rescued HGPS patients-derived fibroblasts from early entry into cellular senescence, which is a downstream event of progerin-induced DNA damage. We also performed a quantitative high-throughput screen (qHTS) of approved drug and investigational agent libraries, leading to the identification of celastrol and AZD1981 as compounds that upregulate {Delta}133p53 protein levels. Methods: To investigate whether celastrol and ADZ1981 upregulate endogenous {Delta}133p53 in HGPS-derived fibroblasts and reduce their senescence-associated phenotypes, we performed western blot assays ({Delta}133p53, progerin, and p21WAF1, which mediates p53-induced senescence and is inhibited by {Delta}133p53), senescence-associated {beta}-galactosidase (SA-{beta}-gal) staining, enzyme-linked immunosorbent assay (IL-6, which is a proinflammatory cytokine secreted from senescent cells), and qRT-PCR assays (p21WAF1 and IL-6). Results: Treatment with celastrol (0.1 M for 24 h) or AZD1981 (10 M for 24 h) reproducibly increased {Delta}133p53 expression and decreased p21WAF1 expression in two strains of fibroblasts derived from HGPS patients. These compounds reduced the percentage of SA-{beta}-gal-positive senescent cells and the secretion of IL-6 into culture medium in both of these fibroblast strains, irrespective of their different basal levels of senescence and IL-6 secretion. These compounds had no effect on the level of progerin. Conclusion: Celastrol and ADZ1981 upregulate endogenous {Delta}133p53 and, reproducing the effects of its vector-driven expression, inhibit cellular senescence and IL-6 secretion in HGPS-derived fibroblasts. Their progerin-independent action suggests that they may synergize with currently available progerin-targeting therapies. This study also warrants further investigation of these compounds for potential applications in other diseases and conditions in which {Delta}133p53-regulated senescence plays a role.
Longevity Relevance Analysis
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Celastrol and AZD1981 upregulate endogenous Δ133p53 and inhibit cellular senescence in fibroblasts derived from HGPS patients. The study addresses a mechanism related to cellular senescence, which is a key aspect of aging and longevity, suggesting potential therapeutic strategies that could impact age-related diseases.
Shigeru Chiba
· International journal of hematology
· Division of Stem Cell Therapy, Institute of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan. [email protected].
· pubmed
Clonal hematopoiesis (CH) has emerged as a common age-related phenomenon and a central concept linking somatic mutations in hematopoietic stem cells to both malignant and non-malignant diseases. While initially recognized in the context of hematologic neoplasms, CH is now known t...
Clonal hematopoiesis (CH) has emerged as a common age-related phenomenon and a central concept linking somatic mutations in hematopoietic stem cells to both malignant and non-malignant diseases. While initially recognized in the context of hematologic neoplasms, CH is now known to contribute to increased all-cause mortality, particularly through heightened risk of cardiovascular and inflammatory diseases. Frequent mutations in genes such as DNMT3A, TET2, and ASXL1 alter epigenetic regulation and immune signaling, thereby promoting clonal expansion and systemic consequences. Longitudinal studies have illuminated the dynamics of clonal growth and revealed how germline variants influence somatic selection. VEXAS syndrome, driven by UBA1-mutated CH, exemplifies the broader clinical reach of clonal expansion beyond malignancy. CH occupies an intermediate biological state with far-reaching implications. In this Progress in Hematology series, contributors explore the natural history, genetic underpinnings, and inflammatory manifestations of CH, offering insights into its role as both a biomarker and a potential therapeutic target in aging populations.
Longevity Relevance Analysis
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Clonal hematopoiesis contributes to increased all-cause mortality and has implications for aging-related diseases. The paper discusses how clonal hematopoiesis links somatic mutations to systemic consequences in aging populations, addressing underlying mechanisms that could inform longevity research.
Nehar-Belaid, D., Thibodeau, A., Eroglu, A. ...
· immunology
· The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032 USA
· biorxiv
The human immune system undergoes continuous remodeling from infancy through old age, yet the timing and trajectory of these changes across the lifespan remain poorly defined. To address this, we profiled peripheral blood mononuclear cells from 95 healthy individuals (ages 2 mont...
The human immune system undergoes continuous remodeling from infancy through old age, yet the timing and trajectory of these changes across the lifespan remain poorly defined. To address this, we profiled peripheral blood mononuclear cells from 95 healthy individuals (ages 2 months to 88 years), including infants (n=27), children (n=23), adults (n=18), and older adults (n=27) using scRNA-seq and snATAC-seq. MAIT and gdT cells showed a rise and fall pattern, which rise in childhood, peak in young adulthood, and decline with age. CD8+ T cells were the most affected by aging with decreasing naive T cells and increasing GzK+ CD8+ T cells and TEMRA cells. Infants had lower myeloid/lymphoid ratio, with a distinct composition marked by increased frequencies of CD16+ monocytes and plasmacytoid dendritic cells and reduced frequencies of CD14+ monocytes and conventional DCs. Their adaptive immune compartment also displayed unique features, including constitutive interferon-stimulated gene expression in T and B cells, and an expanded SOX4+ populations in naive CD4+, naive CD8+ and gdT cells, comprising ~30% of the naive T cell pool. SOX4+ naive CD4+ T cells displayed a Th2 epigenetic signature. This map provides critical insights into human immune system dynamics across the lifespan, emphasizing unique features of the infant immune system.
Longevity Relevance Analysis
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The paper identifies unique immune signatures in infants and characterizes the changes in the immune system across the lifespan. This research is relevant as it provides insights into the fundamental dynamics of the immune system, which could inform strategies for addressing age-related immune decline and longevity.
Ali, M., Li, F., Katari, M. S.
· bioinformatics
· New York University
· biorxiv
Identifying the set of genes that regulate baseline healthy aging - aging that is not confounded by illness - is critical to understating aging biology. Machine learning-based age-estimators (such as epigenetic clocks) offer a robust method for capturing biomarkers that strongly ...
Identifying the set of genes that regulate baseline healthy aging - aging that is not confounded by illness - is critical to understating aging biology. Machine learning-based age-estimators (such as epigenetic clocks) offer a robust method for capturing biomarkers that strongly correlate with age. In principle, we can use these estimators to find novel targets for aging research, which can then be used for developing drugs that can extend the healthspan. However, methylation-based clocks do not provide direct mechanistic insight into aging, limiting their utility for drug discovery. Here, we describe a method for building tissue-specific bulk RNA-seq-based age-estimators that can be used to identify the ageprint. The ageprint is a set of genes that drive baseline healthy aging in a tissue-specific, developmentally-linked fashion. Using our age estimator, SkeletAge, we narrowed down the ageprint of human skeletal muscles to 128 genes, of which 26 genes have never been studied in the context of aging or aging-associated phenotypes. The ageprint of skeletal muscles can be linked to known phenotypes of skeletal muscle aging and development, which further supports our hypothesis that the ageprint genes drive (healthy) aging along the growth-development-aging axis, which is separate from (biological) aging that takes place due to illness or stochastic damage. Lastly, we show that using our method, we can find druggable targets for aging research and use the ageprint to accurately assess the effect of therapeutic interventions, which can further accelerate the discovery of longevity-enhancing drugs.
Longevity Relevance Analysis
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The paper claims to identify a set of 26 novel genes that drive healthy aging in skeletal muscle, which can be targeted for drug discovery. This research is relevant as it seeks to understand the biological mechanisms of aging and identifies potential therapeutic targets to extend healthspan, rather than merely addressing age-related diseases.
Olivier Dionne, Benoit Laurent
· Aging
· Department of Biochemistry and Functional Genomics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.
· pubmed
Ribosome stalling drives aging in the killifish brain.
Ribosome stalling drives aging in the killifish brain.
Longevity Relevance Analysis
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Ribosome stalling contributes to aging in the killifish brain. This research addresses a potential root cause of aging by exploring the mechanisms of ribosome stalling, which could lead to insights into lifespan extension and age-related cellular processes.