Wang, J., Cai, Z., Gu, J. ...
· physiology
· Hunan Normal University
· biorxiv
Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes critical for physiological homeostasis and organismal ageing. While mTORC1 preferentially regulates the translation of 5\'-terminal oligopyrimidine (TOP) motif-conta...
Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes critical for physiological homeostasis and organismal ageing. While mTORC1 preferentially regulates the translation of 5\'-terminal oligopyrimidine (TOP) motif-containing mRNAs that predominantly encode ribosomal proteins (RPs) via the translational repressor 4E-BP, this mTORC1 function is resistant to rapamycin inhibition. TOP mRNAs are exceptionally abundant, thus imposing a major translational burden on cells; yet how their translation is physiologically tuned and linked to longevity remain unexplored. Here we identify Lsp2, originally known as a storage protein, as an adipose effector of mTORC1 that modulates lifespan in Drosophila. Lsp2 is induced by essential amino acids (EAAs) via mTORC1. Genetic ablation of Lsp2 to blunt organismal response to protein diets drives robust lifespan extension without compromising key life-history traits such as reproduction. Translatomic profiling reveals that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan via a mechanism distinct from rapamycin inhibition that fails to reduce 4E-BP phosphorylation in vivo. Finally, Lsp2 adipokine promotes 4E-BP phosphorylation and acts systemically across tissues to shape the lifespan responses to dietary protein. Collectively, our findings establish Lsp2 as a novel translational regulator of TOP genes that mechanistically couples physiological ribosomal protein synthesis with organismal longevity.
Longevity Relevance Analysis
(4)
The paper claims that the adipose mTORC1 effector Lsp2 modulates lifespan in Drosophila by regulating the translation of TOP mRNAs. This research is relevant as it explores a mechanism linking nutrient sensing and ribosomal protein synthesis to longevity, addressing fundamental aspects of aging biology.
Jiayu Guo, Yan Wang, Qiudi Liu ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· State Key Laboratory of Frigid Zone Cardiovascular Diseases (SKLFZCD), Department of Pharmacology (State Key Laboratory-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
· pubmed
Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease. While advancing age is recognized as the most significant risk factor for both the development and mortality associated with pulmonary fibrosis, precise mechanisms underlying th...
Idiopathic pulmonary fibrosis (IPF) is a prototype of chronic, progressive, and fibrotic lung disease. While advancing age is recognized as the most significant risk factor for both the development and mortality associated with pulmonary fibrosis, precise mechanisms underlying this association remain elusive. Here, Nephronectin (NPNT) is identified as an antiaging molecule, a potential major regulator of the progression of pulmonary fibrosis. In IPF patients, a marked reduction in NPNT expression is detected in lung tissues, which correlated with a decline in lung function. The study reveals that NPNT deficiency exacerbates bleomycin-induced senescence in alveolar epithelial cells, potentially intensifying fibrosis severity due to diminishes extracellular matrix turnover. Conversely, NPNT overexpression in the alveolar epithelium improves lung respiratory function and enhances resistance to aging and fibrosis. Mechanistically, NPNT inhibits the hyperactivation of LATS1 and MOB1, facilitates YAP1 nuclear translocation, and suppresses YAP1 ubiquitination and degradation, contingent upon the interaction between NPNT and ITGA3. Notably, pharmacological elevation of NPNT protein levels using Escin has been shown to alleviate pulmonary fibrosis and improve lung function in mice. The findings shed light on the key mechanism underlying stress-induced senescence and fibrosis, and offer a promising framework for interventions targeting aging-related diseases.
Longevity Relevance Analysis
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Nephronectin (NPNT) is identified as a crucial regulator of cellular senescence and pulmonary fibrosis, suggesting its potential role in addressing aging-related mechanisms. The study focuses on NPNT's role in modulating cellular senescence and its implications for aging and fibrosis, which aligns with the exploration of root causes of age-related diseases.
Ye, Y., Ming, D.
· bioinformatics
· Nanjing Tech University
· biorxiv
Senolytics, a category of drugs targeting aging processes, have garnered significant attention since their emergence in 2015. Unlike traditional drug development approaches that rely on randomized screening, research on aging-related pharmaceuticals has employed mechanism-based s...
Senolytics, a category of drugs targeting aging processes, have garnered significant attention since their emergence in 2015. Unlike traditional drug development approaches that rely on randomized screening, research on aging-related pharmaceuticals has employed mechanism-based strategies, resulting in the discovery of the pioneering combination therapy of dasatinib (D) and quercetin (Q). Although preliminary studies with senolytic drug combinations have shown promising outcomes, the predictive capabilities of the research in this field remain limited by the extensive experimental data requirements. In this study, we employed differential gene expression analysis and machine learning techniques to investigate the combinatorial effects of senolytic drugs. We identified 1624 core aging-related genes and used this dataset to retrain a multimodal attention mechanism model, creating a specialized framework: SenolyticSynergy for predicting effective senolytic drug combinations. We then utilized 63 established senolytic compounds as starting points for combination testing, developing a comprehensive dataset of 1953 potential drug combinations for aging interventions. Following rigorous filtration, we identified 190 high-confidence drug combinations and predicted their synergistic scores. Among these combinations, ten demonstrated exceptionally high synergistic scores, exceeding 8. The combination of temsirolimus and nitazoxanide ranked first and may be the most promising candidate. The analysis of literature data and computational studies of molecular structures using 3D modeling validated the accuracy of these predictions. This framework paves the way for large-scale research into anti-aging drug combinations, advancing research capabilities in this field.
Longevity Relevance Analysis
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The paper claims to have developed a framework for predicting effective senolytic drug combinations that target aging processes. This research is relevant as it focuses on identifying drug combinations that may directly address the underlying mechanisms of aging, rather than merely treating age-related diseases.
Jiaojiao Xie, Taewan Kim, Zhongmao Liu ...
· mSystems
· The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
· pubmed
The gut microbiota evolves over a lifetime and significantly impacts the aging process. Targeting the gut microbiota represents a novel avenue to delay aging and aging-related physical and mental decline. However, the underlying mechanism by which the microbiota modulates the agi...
The gut microbiota evolves over a lifetime and significantly impacts the aging process. Targeting the gut microbiota represents a novel avenue to delay aging and aging-related physical and mental decline. However, the underlying mechanism by which the microbiota modulates the aging process, particularly age-related physical and behavioral changes is not completely understood. We conducted fecal microbiota transplantation (FMT) from young or old male donor mice to the old male recipients. Old recipients with young microbiota had a higher alpha diversity than the old recipients with old microbiota. Compared to FMT with old microbiota, FMT with young microbiota reduced body weight and prevented fat accumulation in the old recipients. FMT with young microbiota also lowered frailty, increased grip strength, and alleviated depression and anxiety-like behavior in the old recipients. Consistent with observed physical changes, untargeted metabolomic analysis of serum and stools revealed that FMT with young microbiota lowered age-related long-chain fatty acid levels and increased amino acid levels in the old recipients. Bulk RNAseq analysis of the amygdala of the brain showed that FMT with young microbiota downregulated inflammatory pathways and upregulated oxidative phosphorylation in the old recipients. Our results demonstrate that FMT with young microbiota has substantial positive influences on age-related body composition, frailty, and psychological behaviors. These effects are associated with changes in host lipid and amino acid metabolism in the periphery and transcriptional regulation of neuroinflammation and energy utilization in the brain.
Longevity Relevance Analysis
(5)
Young gut microbiota transplantation improves metabolic health and reduces frailty in old mice. The study addresses the underlying mechanisms of aging by demonstrating how altering gut microbiota can positively influence age-related physical and psychological decline, which is directly relevant to longevity research.
Masaya Hane, Ayane Naramura, Kaito Hayakawa ...
· Sialic Acids
· Integrated Glyco-Biomedical Research Center (iGMED), Institute for Glyco-core Research (iGCORE), Nagoya University, Nagoya, 464-8601, Japan.
· pubmed
Polysialic acid (polySia), a glycoepitope critical for neural development and plasticity, remains difficult to quantify owing to its structural complexity. Here, we present a highly sensitive sandwich enzyme-linked immunosorbent assay (ELISA) utilizing novel probes to measure pol...
Polysialic acid (polySia), a glycoepitope critical for neural development and plasticity, remains difficult to quantify owing to its structural complexity. Here, we present a highly sensitive sandwich enzyme-linked immunosorbent assay (ELISA) utilizing novel probes to measure polySia expression. Using this method, we quantified polySia levels in mouse brain samples across various developmental and aging stages. Notable age-related changes were observed, particularly in neuroplastic regions such as the hippocampus and olfactory bulb, where polySia levels increased at 12 months, potentially reflecting resilience mechanisms against brain aging. Elevated polySia levels in blood samples were also detected in both a schizophrenia mouse model and human patients, with a notable male preponderance. In contrast, no significant changes were observed in patients with chronic inflammatory demyelinating polyneuropathy. These findings, enabled by the novel probes, highlight a potential role for polySia in brain aging and neuropsychiatric disorders, offering new insights into developmental and disease mechanisms and supporting its utility as a diagnostic biomarker for brain impairments.
Longevity Relevance Analysis
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The paper claims that polysialic acid levels change significantly with aging and in neuropsychiatric disorders, suggesting its potential role as a biomarker for brain impairments. The research addresses changes in a glycoepitope associated with neural plasticity and aging, which could provide insights into mechanisms underlying age-related cognitive decline.
Jing Wang, Xiaolan Zhou, Peng Yu ...
· Nature aging
· State Key Laboratory of Genetics and Development of Complex Phenotypes, National Clinical Research Center for Aging and Medicine, Huashan Hospital, Collaborative Innovation Center of Genetics and Development, Human Phenome Institute, Center for Evolutionary Biology, Shanghai Engineering Research Center of Industrial Microorganisms, School of Life Sciences, Fudan University, Shanghai, China.
· pubmed
Despite the manifestation and contribution of cellular senescence to aging and various diseases, accurate identification of heterogeneous senescent cells remains challenging. Current senescence evaluation methods rely mainly on limited markers or homogeneous samples, which might ...
Despite the manifestation and contribution of cellular senescence to aging and various diseases, accurate identification of heterogeneous senescent cells remains challenging. Current senescence evaluation methods rely mainly on limited markers or homogeneous samples, which might fail to capture universal senescence features, limiting their generalizability. Here we developed the human universal senescence index (hUSI), an accurate and robust senescence evaluation method for diverse cells and samples. Based on features learned from the most comprehensive cellular senescence-associated transcriptome data so far, hUSI demonstrated its convincing connections with senescence phenotypes and superior robustness in predicting senescence state. Using hUSI, we discovered potential senescence regulators and mapped senescent cell accumulation across cell types in coronavirus disease 2019 (COVID-19). The method also facilitates decoding heterogeneous senescence states in melanoma tumors, identifying prognosis-associated signaling pathways. Overall, hUSI demonstrates its utility in characterizing cellular senescence across biological contexts, with broad applications in aging research and clinical practice.
Longevity Relevance Analysis
(4)
The paper claims that the human universal senescence index (hUSI) can accurately predict cellular senescence across diverse conditions. This research is relevant as it addresses the identification and characterization of cellular senescence, which is a fundamental aspect of aging and its associated diseases, potentially leading to insights that could inform interventions targeting the aging process itself.
Zhiming Liu, Gang Du, Yi Chen ...
· PLoS genetics
· West China Centre of Excellence for Pancreatitis, and Laboratory of Metabolism and Aging, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Respiratory Health and Multimorbidity and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
· pubmed
The decline in adult stem cell performance is closely linked to tissue malfunction and the rising incidence of age-related diseases. To investigate the molecular basis of these impairments, our screening strategy identified reduced activity in the pantothenate/coenzyme A (CoA) pa...
The decline in adult stem cell performance is closely linked to tissue malfunction and the rising incidence of age-related diseases. To investigate the molecular basis of these impairments, our screening strategy identified reduced activity in the pantothenate/coenzyme A (CoA) pathway within aged ISCs. Furthermore, exogenous CoA supplementation restructured ISC metabolic pathways, reversing age-induced hyperproliferation and intestinal dysfunction, and thus extending Drosophila lifespan by curbing excessive iron accumulation in ISCs. These findings uncover a new mechanism of stem cell aging and propose that pantothenate and CoA could be potential therapeutic targets for treating age-related diseases and enhancing healthy aging in humans.
Longevity Relevance Analysis
(4)
The paper claims that age-associated decline of Coenzyme A leads to intestinal stem cell dysfunction, which can be reversed by CoA supplementation. This research is relevant as it investigates a potential root cause of aging-related decline in stem cell function and proposes a therapeutic target for enhancing healthy aging.
Simmons, S. R., Rivera, A., Ghanem, E. N. B.
· immunology
· University at Buffalo
· biorxiv
The decline in neutrophil antimicrobial function renders vaccinated aged hosts less protected against Streptococcus pneumoniae infection. In vaccinated hosts, activation of neutrophils via phagocytic receptors, like complement and Fc{gamma} receptors, mediates bacterial uptake an...
The decline in neutrophil antimicrobial function renders vaccinated aged hosts less protected against Streptococcus pneumoniae infection. In vaccinated hosts, activation of neutrophils via phagocytic receptors, like complement and Fc{gamma} receptors, mediates bacterial uptake and killing. However, the mechanisms behind changes in signaling downstream of these receptors with age is not known. Mitogen-activated protein kinases (MAPK) are signaling cascades activated in response to cell surface receptors. Using bone marrow neutrophils isolated from young and aged mice, and MAPK phosphorylation array, we found differences in MAPK activation in an opsonin dependent manner (complement vs antibody). Neutrophils from aged mice failed to increase MAPK phosphorylation upon infection with pneumococci opsonized with heat-inactivated (HI) sera from hosts immunized with the pneumococcal conjugate vaccine (PCV), indicating an age-related defect in Fc{gamma}R signaling. Neutrophils from aged mice had higher basal levels of MAPK phosphorylation when compared to young controls, including a 15-fold increase in ERK1/2 phosphorylation. Inhibition of ERK1/2 signaling blunted pneumococcal killing by PMNs from young mice, but improved killing by neutrophils from aged mice, only when the bacteria were opsonized with HI immune but not naive sera. In young human participants, in vitro inhibition of ERK1/2 in neutrophils resulted in decreased pneumococcal killing, but only following PCV vaccination, suggesting that the effects of ERK1/2 inhibition are clinically relevant in vaccinated hosts. This study identifies age-related changes in ERK1/2 activation and demonstrates that balanced activation of this pathway is crucial for neutrophil antimicrobial activity against antibody opsonized bacteria following vaccination in both mice and humans.
Longevity Relevance Analysis
(4)
The paper claims that age-related changes in ERK1/2 activation affect neutrophil antimicrobial activity against antibody opsonized bacteria. This research is relevant as it explores the underlying mechanisms of immune dysfunction in aging, which could contribute to understanding and potentially mitigating age-related declines in immune function.
Yejin Cho, Woo Jin Lee, Hee Soo Kim ...
· GeroScience
· Aging Research Group, Korea Food Research Institute, Wanju-gun, South Korea.
· pubmed
Sarcopenia, a condition characterized by the loss of muscle mass and function with aging, is linked to various health issues including diabetes and increased risk of falls and fractures. Currently, there is no FDA-approved treatment exists for sarcopenia. Citrinin, a natural comp...
Sarcopenia, a condition characterized by the loss of muscle mass and function with aging, is linked to various health issues including diabetes and increased risk of falls and fractures. Currently, there is no FDA-approved treatment exists for sarcopenia. Citrinin, a natural compound present in daily dietary sources such as grains, has not been well characterized for its biological effects on muscle aging. Here, we found that citrinin exhibits beneficial effects in delaying muscle aging in both Caenorhabditis elegans (C. elegans) and mouse muscle cells (C2C12). Citrinin attenuated the decline of muscle activities in aged C. elegans, including pharyngeal pumping, body bending, maximum velocity, and locomotor abilities. It also prevented myosin protein loss in C. elegans muscle cells. Citrinin activated SKN-1 (the C. elegans ortholog of mammalian Nrf2), which mediated the prevention of myosin protein loss and the decline in muscle activities. Additionally, citrinin extended the median lifespan of C. elegans via SKN-1. Furthermore, we found that IRE-1 mediated the effects of citrinin on SKN-1 activation and that citrinin delayed aging through the IRE-1/SKN-1 pathway. However, citrinin prevented muscle aging in a UPR
Longevity Relevance Analysis
(4)
Citrinin delays muscle aging and extends lifespan in C. elegans through SKN-1/Nrf2 activation. The study addresses the root causes of muscle aging and lifespan extension, making it relevant to longevity research.
Priyankaa Bhatia, Judith Tafur, Ruchi Amin ...
· Oocytes
· Department of Cell Biology, Department of Biophysics, UT Southwestern Medical Center, Dallas, TX, USA.
· pubmed
Animals store oocytes in a dormant state for weeks to decades before ovulation. The homeostatic programs that oocytes use to endure long-term storage are poorly understood. Using female nematodes as a short-lived model, we found that oocyte formation and storage required IFET-1, ...
Animals store oocytes in a dormant state for weeks to decades before ovulation. The homeostatic programs that oocytes use to endure long-term storage are poorly understood. Using female nematodes as a short-lived model, we found that oocyte formation and storage required IFET-1, the conserved eIF4E-transporter protein (eIF4ET). IFET-1 co-assembled with CAR-1 (Lsm14) to form micron-scale condensates in stored oocytes, which dissipated after oocyte activation. Depletion of IFET-1 destabilized the stored oocyte proteome, leading to lower translation, a decline in microtubule maintenance proteins, and errors in microtubule organization and meiotic spindle assembly. Deleting domains within IFET-1 impaired oocyte storage without affecting oocyte formation. Thus, in addition to establishing a healthy oocyte reserve in young mothers, IFET-1 ensures that correct levels of cytoskeletal proteins are maintained as oocytes age. eIF4ET also localized to micron-scale puncta in dormant human oocytes. Our results clarify how eIF4ET maintains the oocyte reserve and further support eIF4ET dysfunction as an upstream cause of embryonic aneuploidy and age-related infertility.
Longevity Relevance Analysis
(4)
The paper claims that the eIF4E-transporter protein IFET-1 is crucial for maintaining the proteome of stored oocytes, which is essential for their longevity and functionality. This research is relevant as it addresses mechanisms that contribute to the preservation of oocyte quality over time, linking to age-related fertility issues and the biological understanding of aging processes in reproductive cells.
Maarouf Baghdadi, Helena Hinterding, Thies Gehrmann ...
· GeroScience
· Max Planck Institute for Biology of Ageing, Cologne, Germany.
· pubmed
Human longevity, which is coupled to compression of age-related disease, is a heritable trait. However, only few common genetic variants have been linked to longevity, suggesting that rare, family-specific variants may also play a role. We therefore investigated whole-genome sequ...
Human longevity, which is coupled to compression of age-related disease, is a heritable trait. However, only few common genetic variants have been linked to longevity, suggesting that rare, family-specific variants may also play a role. We therefore investigated whole-genome sequencing data of long-lived individuals from the Leiden Longevity Study and identified family-specific variants residing in genes involved in the mitogen-activated protein kinase (MAPK) cascade, a lifespan-associated and evolutionarily conserved pathway emerging from studies in model organisms. We subsequently generated and functionally characterised mouse embryonic stem cells (mESCs) harbouring these variants. Two variants, located in NF1 (Phe1112Leu) and RAF1 (Asp633Tyr), reduce MAPK/extracellular signal-regulated kinase (ERK) signalling pathway activity in mESCs. At the proteomic and transcriptomic level, we observed prominent changes that were shared (e.g. upregulation of ribosomal proteins and Foxo3 expression) and opposing between the variants (e.g. downregulation of mTORC1 signalling-related proteins and Ets2 expression in the RAF1
Longevity Relevance Analysis
(4)
The paper claims that rare genetic variants in the MAPK/ERK signalling pathway are associated with longevity and affect cellular signaling in mouse embryonic stem cells. This research is relevant as it explores genetic factors that may contribute to the biological mechanisms of aging and longevity, potentially offering insights into the root causes of aging rather than merely addressing age-related diseases.
Mega Obukohwo Oyovwi, Ejime A Chijiokwu, Arientare Rume Rotu ...
· Journal of assisted reproduction and genetics
· Department of Physiology, Faculty of Basic Medical Sciences, Adeleke University, Ede, Osun, Nigeria. [email protected].
· pubmed
The intersection of aging and reproductive decline presents a significant challenge in human health, with fertility rates decreasing sharply in later life for both sexes. This review delves into the intricate relationship between germ cells, the fundamental units of reproduction,...
The intersection of aging and reproductive decline presents a significant challenge in human health, with fertility rates decreasing sharply in later life for both sexes. This review delves into the intricate relationship between germ cells, the fundamental units of reproduction, and their surrounding microenvironment, known as the niche. Emphasizing that reproductive longevity is not solely determined by the intrinsic properties of germ cells, but rather by the complex interplay with their niche, a dynamic system that changes with age. We highlight evidence from model organisms like Drosophila and C. elegans demonstrating how age-related changes in niche signaling impact germ cell function. A systems biology approach, integrating multi-omics data (genetics, epigenetics, cellular behavior), is crucial to fully understanding this complex interaction. Specifically, we discuss the role of epigenetic modifications, such as DNA methylation and histone acetylation, in modulating niche-germ cell communication. This approach offers a comprehensive view of the aging reproductive system and opens up avenues for therapeutic interventions aimed at modulating the niche and potentially extending reproductive lifespan. Future research focused on unraveling the specific molecular mechanisms underlying the niche-germ cell interaction will be pivotal in developing strategies to combat age-related reproductive decline.
Longevity Relevance Analysis
(4)
The paper claims that the aging niche significantly influences germ cell function and reproductive longevity. This research is relevant as it addresses the complex interactions between aging and reproductive decline, focusing on potential interventions to extend reproductive lifespan, which aligns with the goals of longevity research.
Fan, W., Ishikawa, M., Raja, E. ...
· developmental biology
· Kyushu University
· biorxiv
The extracellular matrix (ECM) is crucial in building the extracellular environment and translating extracellular information into biochemical signals that sustain organ functions. Fibulin-5 (Fbln5) is a multifunctional ECM protein essential for forming elastic fibers and regulat...
The extracellular matrix (ECM) is crucial in building the extracellular environment and translating extracellular information into biochemical signals that sustain organ functions. Fibulin-5 (Fbln5) is a multifunctional ECM protein essential for forming elastic fibers and regulating cellular functions by binding to integrins. While fibulin-5 expression decreases with age in human skin, the functional implications of this decrease, particularly in epidermal stem cell regulation, have remained largely unexplored. Here, we find that the knocking out of Fbln5 in mice results in early impairments of epidermal stem cell properties, similar to the chronological aging of the skin. The Fbln5 deficiency suppresses the expression of integrins and other cell junction proteins, leading to the inactivation of YAP signaling in epidermal stem cells. This reduction in YAP signaling results in the downregulation of the fast-cycling epidermal stem cell marker SLC1A3 in human skin and primary keratinocytes. These results suggest that, in addition to its known function in elastic fiber formation, fibulin-5 also plays a critical role in regulating the balance of epidermal stem cell populations during skin aging and coordinating the crosstalk between the extracellular environment and intracellular signaling.
Longevity Relevance Analysis
(4)
Fibulin-5 regulates epidermal stem cell populations during skin aging by influencing integrin expression and YAP signaling. The study addresses a mechanism related to the aging process, specifically how extracellular matrix components affect stem cell function, which is crucial for understanding and potentially mitigating age-related decline in skin health.
Martin, M. S., Bayaraa, N., Fox, B. ...
· biochemistry
· Tufts University
· biorxiv
Glycation is a non-enzymatic post-translational modification associated with aging and disease. Because it occurs spontaneously, it is extremely difficult to control the extent of glycation at distinct sites within target proteins, especially in cellular systems. Here we report a...
Glycation is a non-enzymatic post-translational modification associated with aging and disease. Because it occurs spontaneously, it is extremely difficult to control the extent of glycation at distinct sites within target proteins, especially in cellular systems. Here we report a chemical approach, referred to as \"dialAGE\", that enables the site-specific control of protein glycation. This unique tool requires the introduction of just a single point mutation that modulates the glycation susceptibility of a nearby arginine. As proof-of-concept, extensive mass spectrometry analysis was performed to confirm that dialAGE can modulate site-specific glycation levels at multiple arginine residues in ubiquitin in vitro, enabling both enhanced and diminished glycation. Introduction of dialAGE point mutations and/or glycation with the biologically relevant glycating agent methylglyoxal did not affect polyubiquitin chain formation using in vitro ubiquitination assays. Furthermore, we show that dialAGE can be used to modulate ubiquitin glycation levels in living mammalian cells. We therefore anticipate that this method will be particularly useful for enabling the study of glycation as a genuine, functional, post-translational modification.
Longevity Relevance Analysis
(4)
The paper claims to provide a method for site-specific control of protein glycation in living cells. This research is relevant as it addresses glycation, a post-translational modification linked to aging and age-related diseases, and offers a potential tool for studying its functional implications in the context of aging.
Xinfeng Bai, Pu Shi, Weihua Chu
· Probiotics
· Shandong Provincial Third Hospital, Shandong University, Jinan, China.
· pubmed
Γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system, has been shown to alleviate various physiological disorders including insomnia, hypertension, depression, and memory loss. Lactic acid bacteria (LAB), recognized as safe GABA producers,...
Γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the central nervous system, has been shown to alleviate various physiological disorders including insomnia, hypertension, depression, and memory loss. Lactic acid bacteria (LAB), recognized as safe GABA producers, have attracted increasing attention. This study aimed to screen GABA-producing LAB from naturally fermented dairy products and evaluate their probiotic potential, antioxidant and neuromodulatory activities, while optimizing GABA production. GABA-producing LAB were screened using the Berthelot method and thin-layer chromatography. The safety of Lactiplantibacillus plantarum SY1 was assessed through hemolysin production and drug sensitivity tests. L. plantarum SY1 demonstrated high tolerance to acidic conditions and low bile salt concentrations, along with significant antioxidant capacity (49 ± 0.2% DPPH radical scavenging rate, 86.1 ± 0.14% hydroxyl radical scavenging rate, and 32.7 ± 1.6% superoxide radical anion scavenging rate). In vivo experiments revealed that L. plantarum SY1 extended the lifespan of C. elegans N2, enhanced oxidative stress resistance, and delayed paralysis in transgenic C. elegans (CL4176) by 23.53%. Through OFAT strategy and RSM optimization, GABA production reached 1.49 g/L under optimal conditions (37℃, pH 4.44, 96 h fermentation, and 4.16% inoculum). These findings demonstrate that L. plantarum SY1 is a promising GABA-producing strain with antioxidant and neuromodulatory effects, suggesting its potential as an anti-aging and neuroprotective probiotic.
Longevity Relevance Analysis
(4)
Lactiplantibacillus plantarum SY1 demonstrates potential as a GABA-producing probiotic with antioxidant and neuromodulatory effects that may contribute to lifespan extension. The study explores mechanisms that could influence aging processes, particularly through the enhancement of oxidative stress resistance and lifespan extension in model organisms.
Samuel Ruiz-Pérez, Nicolás Alcaraz, Karla Torres-Arciga ...
· Advanced biology
· Laboratorio de Regulación de la Cromatina y Genómica, Instituto Nacional de Cancerología, Av. San Fernando 22, Belisario Domínguez Sección XVI, Tlalpan, Ciudad de México, 14080, Mexico.
· pubmed
The axolotl (Ambystoma mexicanum) has a great capacity to regenerate its tissues; however, the fidelity and success of its regenerative process diminish with age. Retrotransposons make up the largest portion of the axolotl genome, and their expression may be involved in this age-...
The axolotl (Ambystoma mexicanum) has a great capacity to regenerate its tissues; however, the fidelity and success of its regenerative process diminish with age. Retrotransposons make up the largest portion of the axolotl genome, and their expression may be involved in this age-related decline. Through an integrative analysis of repetitive element expression using RNA sequencing, it is shown that Ty3 retrotransposons are highly upregulated in the axolotl as an effect of chronological aging. Other non-long-terminal-repeat transposons, including long interspersed nuclear element 1, function as hubs of gene coexpression networks involved in muscle development and regulation of apoptosis and connective tissue replacement, which are also suppressed in adulthood. By contrast, it is found that during regeneration of the limb, these pathways and the expression of Ty3 retrotransposons are distinctly downregulated. Although the blastema can readjust most of the transposon differential expression in adulthood, several elements remain affected and may have an impact in the immune response during regeneration. This analysis provides a profile of retrotransposon expression through chronological aging and during limb regeneration in the axolotl and indicates that transposons are responsive to physiological changes in a tissue-specific way and may participate in the gene coregulatory networks underlying the regenerative process.
Longevity Relevance Analysis
(4)
The paper claims that retrotransposon expression is upregulated with aging in axolotls and is suppressed during limb regeneration. This research is relevant as it explores the molecular mechanisms underlying aging and regeneration, potentially contributing to understanding the root causes of age-related decline in regenerative capacity.
Ruin Moaddel, Chad Sanehira, Gregory Keyes ...
· npj aging
· Laboratory of Clinical Investigation, National Institute on Aging, Intramural Research Program, NIH, Baltimore, MD, USA. [email protected].
· pubmed
Senescent cells accumulate with aging and are associated with several age-associated diseases and functional declines. Eliminating senescent cells with senolytics improves aging phenotypes in mouse models and may improve the health of people with chronic diseases. To date, very f...
Senescent cells accumulate with aging and are associated with several age-associated diseases and functional declines. Eliminating senescent cells with senolytics improves aging phenotypes in mouse models and may improve the health of people with chronic diseases. To date, very few senotherapeutic (senolytics and senomorphics) compounds have been identified. In a recent study, we reported that gingerenone A (GinA) has a senolytic effect via mechanisms including the activation of caspase-3 activity and apoptotic cell death. In this study, we investigated whether GinA has senotherapeutic properties in a mouse model of senescence. Moreover, we modified GinA with eicosapentaenoic acid (EPA) esters (GinA-EPA) or docosahexaenoic acid (DHA) esters (GinA-DHA) to generate modified gingerenone A (modGinA) that could enhance GinA effects. We found that both GinA and modGinA induced biochemical and histological changes consistent with anti-inflammatory, senolytic, and senomorphic effects, leading to improved metabolic and mitochondrial functions.
Longevity Relevance Analysis
(4)
Modified gingerenone A exhibits senolytic effects that may improve metabolic and mitochondrial functions in a mouse model of senescence. The study addresses the accumulation of senescent cells, which is a root cause of aging and age-related diseases, making it relevant to longevity research.
Yuanxin Miao, Yan Xu, Jia Gao ...
· NPJ science of food
· Functional Exploration and Comprehensive Utilization Team for Specialty Foods, Jingchu University of Technology, Jingmen, China.
· pubmed
Chinese olive (Canarium album L.) contains various phytochemical compositions, exhibiting multiple health-promoting bioactivities. In this study, we used Caenorhabditis elegans (C. elegans) as model organisms to investigate the anti-aging functions of Chinese olive fruit extract ...
Chinese olive (Canarium album L.) contains various phytochemical compositions, exhibiting multiple health-promoting bioactivities. In this study, we used Caenorhabditis elegans (C. elegans) as model organisms to investigate the anti-aging functions of Chinese olive fruit extract (COFE). The results showed that COFE contained large amounts of flavonoids and polyphenols, and thus it could strengthen stress resistance, delay aging, and promote the health of C. elegans. Furthermore, COFE improved the locomotion ability of C. elegans and reduced lipofuscin deposition. COFE also prolonged the survival time of C. elegans by affecting the Insulin/IGF-1 signaling pathway, DAF-16/FOXO, and SKN-1/Nrf2 transcription factors. Transcriptome analysis indicated that COFE treatment induced differential expression of genes related to defense response, immune response, stress response, oxidoreductase activity, and intracellular oxygen homeostasis in C. elegans. The positive results provide a theoretical basis and valuable reference for developing Chinese olive into functional food to delay aging and treat aging-related diseases.
Longevity Relevance Analysis
(4)
Chinese olive fruit extract prolongs lifespan in C. elegans by modulating key signaling pathways associated with aging. The study directly investigates mechanisms that may contribute to lifespan extension and aging delay, aligning with the goals of longevity research.
Prajakta Tiwari, Shreesh Kumar Shukla, Smita Rastogi Verma
· Neoplasms
· Department of Biotechnology, Delhi Technological University, Delhi, 110042, India.
· pubmed
Senescence is a pivotal cellular process, which also plays a major role in development, immune regulation, tissue repair, and aging, triggered by stressors such as telomere shortening, oncogene activation, and DNA damage. Characterized by distinct morphological and molecular feat...
Senescence is a pivotal cellular process, which also plays a major role in development, immune regulation, tissue repair, and aging, triggered by stressors such as telomere shortening, oncogene activation, and DNA damage. Characterized by distinct morphological and molecular features, senescence is known to act as a tumor suppressive mechanism through irreversible cell cycle arrest. However, emerging studies reveal a paradox: prolonged senescence in cancer cells can drive tumorigenesis via the senescence-associated secretory phenotype, promoting proliferation, invasion, and metastasis. This comprehensive review elucidates the molecular intricacies of senescence to induce growth arrest, enhance immune surveillance, and favorably modulate the tumor microenvironment to inhibit cancer progression. Additionally, it examines the senescence-inducing effects of conventional therapies and explores the potential of emerging therapies, including targeted therapies and chimeric antigen receptor T cell therapy. The present review also highlights the promise of senotherapeutic strategies in selectively targeting senescent cells to improve therapeutic outcomes. It discusses the innovative integration of machine learning tools for biomarker discovery and patient stratification offering a transformative approach to improve cancer treatment efficacy.
Longevity Relevance Analysis
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The paper discusses the complexities of cellular senescence and its dual role in cancer, emphasizing therapeutic opportunities to target senescent cells. This is relevant as it addresses mechanisms that could potentially mitigate age-related processes and improve longevity through innovative therapeutic strategies.
Kevin O Murray, Sophia A Mahoney, Katelyn R Ludwig ...
· Aging cell
· Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, USA.
· pubmed
Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to...
Excess cellular senescence contributes to age-related increases in frailty and reductions in skeletal muscle strength. In the present study, we determined the efficacy of oral intermittent treatment (1 week on-2 weeks off-1 week on) with the natural flavonoid senolytic fisetin to improve frailty and grip strength in old mice. Further, the effects of fisetin on physical function were evaluated in young mice. We performed bulk RNA sequencing of quadricep skeletal muscle to determine the cell senescence-related signaling pathways modulated by fisetin. We also assessed the relative effects of fisetin on frailty and grip strength with aging in comparison with two other well-established approaches for the removal of senescent cells: (1) genetic-based clearance of excess senescent cells in old p16-3MR mice, a model that allows for clearance of p16-positive (p16+) senescent cells, and (2) oral intermittent treatment with the synthetic pharmacological senolytic ABT-263 in old mice. We found that fisetin mitigated the adverse changes in frailty and grip strength with aging. Fisetin had no effects in young mice. The improvements in frailty and grip strength in old mice were accompanied by favorable modulation of the skeletal muscle transcriptome, including lower abundance of cellular senescence-related genes (e.g., Cdkn1a and Ddit4). Improvements in frailty and grip strength with fisetin were comparable to those observed with genetic-based clearance of excess p16+ senescent cells and treatment with ABT-263. Taken together, our findings provide proof-of-concept support for fisetin as a senolytic strategy to improve physical function with aging.
Longevity Relevance Analysis
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Intermittent supplementation with fisetin improves physical function and decreases cellular senescence in skeletal muscle with aging. The study addresses the root causes of aging by exploring the senolytic effects of fisetin, which may contribute to improved physical function and reduced frailty in older individuals.
Mingtong, G., Alfatah, M.
· genetics
· Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117544, Singapore
· biorxiv
Aging involves cellular decline and reduced stress resilience. We investigated geroprotective interventions using the yeast chronological aging model and identified methyl nicotinate (MN) as a potent lifespan-extending compound. MN enhanced cellular lifespan and stress resistance...
Aging involves cellular decline and reduced stress resilience. We investigated geroprotective interventions using the yeast chronological aging model and identified methyl nicotinate (MN) as a potent lifespan-extending compound. MN enhanced cellular lifespan and stress resistance through mitochondria-dependent mechanisms, including AMPK/SNF1 signaling and HAP4-mediated mitochondrial biogenesis. These benefits extended to human cells, improving their survival and mitochondrial function under aging conditions. Importantly, the effects of MN are linked to the NAD biosynthetic pathway, with its conversion to nicotinic acid (NA) and subsequent entry into the NAD salvage pathway being essential. We also identified the esterase IAH1 as a key enzyme for converting MN to NA in yeast. Our findings reveal MN as a conserved longevity compound, offering a new avenue for NAD+ modulating anti-aging strategies.
Longevity Relevance Analysis
(5)
Methyl nicotinate promotes lifespan extension through mitochondria-dependent mechanisms in yeast and human cells. The paper addresses the root causes of aging by identifying a compound that enhances cellular lifespan and stress resistance, contributing to the understanding of geroprotective interventions.
Lisonia Gkioni, Tobias Nespital, Maarouf Baghdadi ...
· Nature aging
· Department Biological Mechanisms of Ageing, Max Planck Institute for Biology of Ageing, Cologne, Germany.
· pubmed
Suppression of the insulin-IGF-mTORC1-Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks ...
Suppression of the insulin-IGF-mTORC1-Ras network ameliorates aging in animals. Many drugs have targets in the network because of its roles in cancer and metabolic disease and are candidates for repurposing as geroprotectors. Rapamycin, an established geroprotective drug, blocks mTORC1 signaling, and trametinib inhibits the Ras-MEK-ERK pathway. In this study, we assessed survival and health of male and female mice treated with trametinib, rapamycin or their combination. We show here that trametinib treatment extended lifespan in both sexes and that its combination with rapamycin was additive. Combination treatment reduced liver tumors in both sexes and spleen tumors in male mice, blocked the age-related increase in brain glucose uptake and strongly reduced inflammation in brain, kidney, spleen and muscle and circulating levels of pro-inflammatory cytokines. We conclude that trametinib is a geroprotector in mice and that its combination with rapamycin is more effective than either drug alone, making the combination a candidate for repurposing as a gerotherapy in humans.
Longevity Relevance Analysis
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The paper claims that the combination of trametinib and rapamycin extends lifespan and healthspan in mice. This study is relevant as it explores potential geroprotective interventions that target the underlying mechanisms of aging, rather than merely addressing age-related diseases.
Panek, J., Sun, C., Kataura, T. ...
· cell biology
· Newcastle University
· biorxiv
Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of...
Autophagy is a critical mechanism of cellular quality control, orchestrated by selective autophagy receptor (SAR) proteins. Pharmacologically enhancing the cargo-targeting capacity of SARs presents an attractive but underexplored strategy for the precise therapeutic activation of autophagy. Here, we characterise SQ-1, a small-molecule activator of autophagy that targets the prototypical SAR protein p62/SQSTM1 (sequestosome-1). We show that SQ-1 sensitises p62 to oxidation and promotes its disulphide-mediated oligomerisation in response to mitochondrial reactive oxygen species (ROS). This ROS-dependent activation of p62-mediated selective autophagy enhances the clearance of ROS-generating mitochondria and restores cell viability in models of Niemann-Pick type C1 (NPC1) disease, which is marked by impaired autophagic flux. In summary, the unique mode of action of SQ-1 enables self-regulated autophagy activation, offering a potential therapeutic strategy for lysosomal storage disorders and a broader spectrum of age-related diseases characterised by defective autophagy.
Longevity Relevance Analysis
(4)
The paper claims that SQ-1 enhances autophagy through p62 oligomerisation, improving cell viability in models of Niemann-Pick type C1 disease. This research addresses the activation of autophagy, a key cellular process linked to aging and age-related diseases, suggesting potential therapeutic strategies that could impact longevity.
Inés Fernández Maestre, Alexander S Harris, Corina Amor
· Genes & development
· Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
· pubmed
The rising global demographic aging and the subsequent increase in the prevalence of age-related diseases highlight the need to understand aging biology. A key player in organismal aging is the immune system, which has broad systemic effects. On the one hand, immune aging involve...
The rising global demographic aging and the subsequent increase in the prevalence of age-related diseases highlight the need to understand aging biology. A key player in organismal aging is the immune system, which has broad systemic effects. On the one hand, immune aging involves the decline of hematopoietic stem cells and significant alterations in the functionality and composition of both innate and adaptive immunity. On the other hand, the aged immune system contributes to chronic inflammation and disrupted tissue homeostasis, thereby driving systemic aging processes. In this review, we examine the close interaction between aging and the immune system and discuss emerging therapeutic strategies aimed at modulating immune function to mitigate age-related pathologies.
Longevity Relevance Analysis
(4)
The paper discusses the interplay between aging and the immune system, highlighting potential therapeutic strategies to modulate immune function in order to mitigate age-related pathologies. This is relevant as it addresses mechanisms underlying aging and seeks to explore interventions that could impact longevity and age-related diseases.
Xu Wang, Dan Guo, Chengmei He ...
· Mesenchymal Stem Cells
· Clinical Biobank, Department Medical Research Central, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
· pubmed
Aging leads to a gradual decline in immune function, termed immunosenescence, which significantly elevates the susceptibility to infections, cancers, and other aging-related diseases. Recent advancements have shed light on the molecular underpinnings of immune aging and pioneered...
Aging leads to a gradual decline in immune function, termed immunosenescence, which significantly elevates the susceptibility to infections, cancers, and other aging-related diseases. Recent advancements have shed light on the molecular underpinnings of immune aging and pioneered novel therapeutic interventions to counteract its effects. Mesenchymal stem cells (MSCs)-a type of multipotent stromal cells with regenerative potential, low immunogenicity, and strong immunomodulatory properties-are increasingly recognized as a promising therapeutic option to reverse or alleviate immunosenescence-related dysfunction. This review systematically summarizes recent discoveries on how MSCs counteract immune aging, particularly their ability to rejuvenate aged immune cells and restore immune homeostasis. It also addresses key challenges, such as variations in MSC sources, donor variability, and the lack of standardized protocols, while proposing future directions to enhance therapeutic precision. Although preclinical and clinical studies highlight the potential of MSC-based strategies for delaying immunosenescence, critical issues remain unresolved, including long-term safety and efficacy, optimizing cell delivery systems, and elucidating context-specific mechanisms. Addressing these challenges will accelerate the development of MSC-based therapies to combat aging-associated immune decline.
Longevity Relevance Analysis
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Mesenchymal stem cells have the potential to rejuvenate aged immune cells and restore immune homeostasis. The paper addresses the root causes of immunosenescence, which is a significant aspect of aging and its associated decline in immune function.
Xu, P., Zhang, H., Zhu, S. ...
· genomics
· Center of Clinical Laboratory Medicine, Zhongda Hospital, School of Medicine, Advanced Institute for Life and Health, Southeast University
· biorxiv
Cellular senescence represents a stable cell cycle arrest state that plays critical roles in tissue aging and age-related pathologies. While single-cell RNA sequencing (scRNA-seq) has enabled comprehensive profiling of millions of cells in aged tissues, reliable identification of...
Cellular senescence represents a stable cell cycle arrest state that plays critical roles in tissue aging and age-related pathologies. While single-cell RNA sequencing (scRNA-seq) has enabled comprehensive profiling of millions of cells in aged tissues, reliable identification of senescent cells remains challenging due to the weak and non-specific expression of marker genes. Although existing computational methods could be used to detect active cell states through gene set scoring approaches, their performance with senescence genes has not been rigorously assessed. In this study, we showed that senescence genes display weak, non-specific expression patterns across different tissues and are susceptible to dropout events in scRNA-seq. Current scoring approaches suffered intrinsic limitations in single-cell detection using weakly expressed markers. Simply expanding the gene set of weak markers failed to improve detection accuracy. To overcome these limitations, we developed ICE (Iterative-imputation-based Cell Enrichment), a computational framework that combines expression imputation with iterative marker refinement. ICE achieved a remarkable improvement in detection precision when analyzing pancreatic cells with weakly expressed markers, by increasing accuracy from 56% to 98%. Applied to senescence markers (CDKN1A/p21, CDKN2A/p16, ATF3, and MX1), ICE successfully identified marker-specific cell populations, including stressed {beta} cells in aging and type-I interferon-responsive microglia in Alzheimer\'s disease (AD). Together, our study offered a rigorous analytical framework for single cell detection using markers with weak expressions, which will facilitate in-depth exploration of senescence heterogeneity and temporal dynamics in human tissue and disease states.
Longevity Relevance Analysis
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The paper claims that the ICE framework significantly improves the detection of senescent cells using weak gene markers in single-cell RNA sequencing. This research is relevant as it addresses the identification of cellular senescence, a fundamental process in aging and age-related diseases, thereby contributing to a better understanding of the mechanisms underlying aging.
Flora, Y., Shastri, D., Bohnert, K. A.
· cell biology
· Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana USA 70803
· biorxiv
Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during e...
Peroxisomes execute essential functions in cells, including detoxification and lipid oxidation. Despite their centrality to cell biology, the relevance of peroxisomes to aging remains understudied. We recently reported that peroxisomes are degraded en masse via pexophagy during early aging in the nematode Caenorhabditis elegans, and we found that downregulating the peroxisome-fission protein PRX-11/PEX11 prevents this age-dependent pexophagy and extends lifespan. Here, we further investigated how prx-11 inhibition promotes longevity. Remarkably, we found that reducing peroxisome degradation with age led to concurrent improvements in another organelle: mitochondria. Animals lacking prx-11 function showed tubular, youthful mitochondria in older ages, and these enhancements required multiple factors involved in mitochondrial tubulation and biogenesis, including FZO-1/Mitofusin, UNC-43 protein kinase, and DAF-16/FOXO. Importantly, mutation of each of these factors negated lifespan extension in prx-11-defective animals, indicating that pexophagy inhibition promotes longevity only if mitochondrial health is co-maintained. Our data support a model in which peroxisomes and mitochondria track together with age and interdependently influence animal lifespan.
Longevity Relevance Analysis
(4)
Inhibition of the peroxisomal protein PRX-11 extends lifespan in Caenorhabditis elegans by enhancing mitochondrial health. This research addresses the mechanisms of aging by exploring the relationship between peroxisomes and mitochondria, contributing to our understanding of longevity and potential interventions in age-related decline.
Carina Kern, Joseph V Bonventre, Alexander W Justin ...
· Oncogene
· LinkGevity, Babraham Research Campus, Cambridge, UK. [email protected].
· pubmed
Necrosis is uncontrolled cell death that marks the irreversible threshold of biological degeneration. Rooted in the Greek nekros (death), it is a pivotal mechanism underlying numerous diseases, including cancer, as well as renal, cardiac, neuronal, and hepatic disorders, and more...
Necrosis is uncontrolled cell death that marks the irreversible threshold of biological degeneration. Rooted in the Greek nekros (death), it is a pivotal mechanism underlying numerous diseases, including cancer, as well as renal, cardiac, neuronal, and hepatic disorders, and more broadly, the aging process. Despite its profound impact on morbidity and mortality, necrosis remains untreatable and has long been viewed as a chaotic, unavoidable aspect of biology. This review examines the mechanisms of necrosis and outlines its far-reaching impact on health, as revealed by emerging evidence. Furthermore, we explore its potential as a game-changing therapeutic target. Inhibiting necrosis could revolutionize treatments for acute and chronic age-related conditions like cancer, kidney disease, cardiovascular disease (including heart attacks and strokes), and neurodegeneration, while also preserving resilience-and even slowing aging itself. Beyond Earth, where microgravity, cosmic radiation, and oxidative stress accelerate cellular decline, targeting necrosis may also hold the key to preserving astronaut resilience and health on long-duration space missions, offering insights that could reshape human longevity both on and off the planet.
Longevity Relevance Analysis
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Inhibiting necrosis could revolutionize treatments for age-related conditions and potentially slow aging itself. The paper addresses the fundamental mechanisms of necrosis as a driver of biological decline, proposing it as a target for interventions that could impact longevity and resilience.
Marc Daniel Opfermann, Maria Bøgelund Søndergård, Louise Vase Bech ...
· Nature chemical biology
· Department of Forensic Medicine, Aarhus University, Aarhus, Denmark.
· pubmed
Methylglyoxal (MG) is a reactive metabolite involved in diabetes and aging through the formation of protein adducts. Less is known about the extent that MG and its metabolic product S-D-lactoylglutathione (LGSH) form adducts with cell metabolites. Using a 'symmetric' isotope-labe...
Methylglyoxal (MG) is a reactive metabolite involved in diabetes and aging through the formation of protein adducts. Less is known about the extent that MG and its metabolic product S-D-lactoylglutathione (LGSH) form adducts with cell metabolites. Using a 'symmetric' isotope-labeled and reactivity-based metabolomics approach in living cells, we found over 200 adducts and, surprisingly, discovered that 10 of the most abundant are lactoylated amino acids mainly derived from LGSH. The most abundant adduct D-Lac-Cys is formed rapidly between LGSH and cysteine, whereas the diastereoisomer L-Lac-Cys is formed directly from MG and cysteine, assigning cysteine with both glyoxalase 1-like and glyoxalase 2-like activity. Cellular cysteine and MG dynamically regulate D-Lac-Cys and L-Lac-Cys levels and the adducts are increased in diabetes, suggesting their use as novel biomarkers. Lastly, cysteine amides, as proxies for protein cysteines, also undergo lactoylation by MG and LGSH, suggesting the existence of two additional pathways for nonenzymatic lactoylation of proteins.
Longevity Relevance Analysis
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The paper claims that cysteine exhibits glyoxalase 1-like and glyoxalase 2-like activities through the formation of lactoylated amino acids, which are increased in diabetes and may serve as novel biomarkers. The research addresses metabolic processes related to aging and diabetes, linking reactive metabolites to potential biomarkers that could inform on aging mechanisms.
Mingyu Xia, Feng Zhang, Jiaoyao Ma ...
· Cell reports
· ENT Institute and Otorhinolaryngology Department of Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200031, China; Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China; NHC Key Laboratory of Hearing Medicine, Fudan University, Shanghai 200031, China.
· pubmed
Degeneration of the auditory and vestibular hair cells (HCs) leads to dysfunction of two essential senses: hearing loss and decompensated balance perception. However, the cellular and molecular mechanisms governing inner ear aging and its link to dysfunctions of sensory HCs remai...
Degeneration of the auditory and vestibular hair cells (HCs) leads to dysfunction of two essential senses: hearing loss and decompensated balance perception. However, the cellular and molecular mechanisms governing inner ear aging and its link to dysfunctions of sensory HCs remain unclear. Here, we constructed an aging-associated cell atlas of cochlear and utricular tissues in C57BL/6J mice through single-nucleus RNA sequencing, revealing transcriptionally distinct hair cell subtypes and spatially restricted molecular markers that delineate specific cellular populations. We uncovered activation of macrophages and shaped inflamed niches in the aged inner ear. Furthermore, we demonstrated the cell type-specific signatures of aging between the two organs, with focused characterization in six HC subtypes uncovering core mechanisms like dysregulated RNA splicing underlying degeneration. Crucially, suppressing RNA splicing factor Rbm25 abolished inflammation-induced HC deterioration. Our study reveals complex, multifactorial mechanisms that underlie inner ear aging and offer potential targets for preventing HC degeneration.
Longevity Relevance Analysis
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The study identifies specific cellular mechanisms and signatures of aging in hair cells of the inner ear, suggesting potential targets for preventing degeneration. This research addresses the underlying mechanisms of aging in sensory cells, which is relevant to understanding and potentially mitigating age-related sensory dysfunctions.
Chen, F., Nam, Q., Wang, L. D. ...
· molecular biology
· Nanyang Technological University
· biorxiv
Lipofuscin, a protein-lipid complex that progressively accumulates in senescent cells, was commonly observed in the liver biopsies from patients with liver fibrosis or cirrhosis regardless of the etiological insults. However, whether and how lipofuscin contributes to the developm...
Lipofuscin, a protein-lipid complex that progressively accumulates in senescent cells, was commonly observed in the liver biopsies from patients with liver fibrosis or cirrhosis regardless of the etiological insults. However, whether and how lipofuscin contributes to the development of liver fibrosis remains unknown. Using a mouse model of liver fibrosis induced by choline-deficient L-amino acid-defined high-fat diet (HFD), we found that lipofuscin accumulation preceded the emergence of liver fibrosis. A significant, positive and strong correlation was observed between the hepatic lipofuscin levels and liver fibrosis severity. Neutrophils were recruited to the liver in mice fed HFD, and those that were in close proximity to lipofuscin-laden hepatocytes displayed higher susceptibility to produce neutrophil extracellular traps (NETs). We revealed that lipofuscin-laden hepatocytes generated CXCL5, which promoted NETosis. When mice defective in NETosis (Vav1-Cre Padi4fl/fl) were fed HFD, they had significantly less collagen deposition in the liver, indicating the critical role of NETs in the development of liver fibrosis associated with lipofuscin accumulation. Notably, we showed that tirzepatide, the latest glucagon-like peptide-1 receptor and glucose-dependent insulinotropic polypeptide receptor dual agonist recently approved for type 2 diabetes, attenuated NETosis-dependent liver fibrosis by preventing hepatic lipofuscin accumulation, and reduced other hepatic senescence signatures as well. In summary, our study unveiled the pathogenic, NETosis-enhancing effect of lipofuscin in liver fibrosis, and demonstrated the potential of repurposing tirzepatide for combating liver fibrosis associated with lipofuscin and for preventing organ senescence.
Longevity Relevance Analysis
(4)
Tirzepatide reduces NETosis-mediated liver fibrosis by preventing hepatic lipofuscin accumulation. The study addresses the role of lipofuscin in liver fibrosis, linking it to senescence and suggesting a therapeutic approach that could impact age-related liver diseases, thus contributing to the understanding of aging mechanisms.
Gupta, R., Durham, T. J., Chau, G. ...
· genetics
· Harvard Medical School
· biorxiv
One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences...
One of the strongest signatures of aging is an accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy. Here we investigate the mechanism underlying this phenomenon by calling mtDNA sequence, abundance, and heteroplasmic variation in human blood using whole genome sequences from ~750,000 individuals. Our analyses reveal a simple, two-step mechanism: first, individual cells randomly accumulate low levels of \"cryptic\" mtDNA mutations; then, when a cell clone proliferates, the cryptic mtDNA variants are carried as passenger mutations and become detectable in whole blood. Four lines of evidence support this model: (1) the mutational spectrum of age-accumulating mtDNA variants is consistent with a well-established model of mtDNA replication errors, (2) these mutations are found primarily at low levels of heteroplasmy and do not show evidence of positive selection, (3) high mtDNA mutation burden tends to co-occur in samples harboring somatic driver mutations for clonal hematopoiesis (CH), and (4) nuclear GWAS reveals that germline variants predisposing to CH (such as those near TERT, TCL1A, and SMC4) also increase mtDNA mutation burden. We propose that the high copy number and high mutation rate of mtDNA make it a particularly sensitive blood-based marker of CH. Importantly, our work helps to mechanistically unify three prominent signatures of aging: common germline variants in TERT, clonal hematopoiesis, and observed mtDNA mutation accrual.
Longevity Relevance Analysis
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The paper claims that age-related accumulation of mitochondrial DNA mutations in blood is driven by a two-step mechanism involving random mutation accumulation and clonal proliferation. This research is relevant as it addresses the underlying mechanisms of aging and proposes a potential biomarker for age-related processes, contributing to the understanding of aging biology.
Zhenguo Wang, Zhe Li, Hongyu Liu ...
· Nature aging
· CAS Key Laboratory of Computational Biology, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
· pubmed
Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-spe...
Mitochondria rapidly accumulate mutations throughout a lifetime, potentially acting as a molecular clock for aging and disease. We profiled mitochondrial RNA across 47 human tissues from 838 individuals, revealing rapid development of clonal mosaicism with two distinct tissue-specific aging signatures. Tissues with constant cellular turnover such as the gastrointestinal tract or skin exhibit accelerated accumulation of sporadic mutations and clonal expansions, implicating increased susceptibility to age-related tumorigenesis and dysfunction. By contrast, post-mitotic tissues, such as the heart and brain, accumulate mutations at deterministic hotspots (tissue-specific, recurrently mutated sites), reflecting the cumulative burden of high energy demand and mitochondrial turnover independent of cell division. These findings support a biphasic model of the mitochondrial clock: stochastic clonal expansion of sporadic replication errors in proliferative tissues, versus age-dependent heteroplasmy increases at hotspots in high-metabolic tissues. This mutational landscape provides a map of tissue-specific vulnerabilities during aging and offers potential therapeutic targets.
Longevity Relevance Analysis
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The paper claims that mitochondrial clonal mosaicism reveals a biphasic molecular clock of aging that varies between proliferative and post-mitotic tissues. This research is relevant as it addresses the underlying mechanisms of aging through mitochondrial mutations, potentially identifying vulnerabilities and therapeutic targets that could influence longevity and age-related diseases.
Shiyi Zhou, Katherine E Novak, Rachel Kaletsky ...
· Nature aging
· Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
· pubmed
While memory regulation is predominantly understood as autonomous to neurons, factors outside the brain can also affect neuronal function. In Caenorhabditis elegans, the insulin/IGF-1-like signaling (IIS) pathway regulates longevity, metabolism and memory: long-lived daf-2 insuli...
While memory regulation is predominantly understood as autonomous to neurons, factors outside the brain can also affect neuronal function. In Caenorhabditis elegans, the insulin/IGF-1-like signaling (IIS) pathway regulates longevity, metabolism and memory: long-lived daf-2 insulin/IGF-1 receptor mutants more than double memory duration after a single training session, and it was assumed that memory regulation was strictly neuronal. However, here we show that degradation of DAF-2 in the hypodermis also greatly extends memory, via expression of the diffusible Notch ligand, OSM-11, which in turn activates Notch signaling in neurons. Single-nucleus RNA sequencing of neurons revealed increased expression of CREB and other memory genes. Furthermore, in aged animals, activation of the hypodermal IIS-Notch pathway as well as OSM-11 overexpression rescue both memory and learning via CREB activity. Thus, insulin signaling in the liver-like hypodermis non-autonomously regulates neuronal function, providing a systemic connection between metabolism and memory through IIS-Notch-CREB signaling from the body to the brain.
Longevity Relevance Analysis
(4)
The paper claims that degradation of DAF-2 in the hypodermis extends memory through systemic signaling pathways involving Notch and CREB activity. This research is relevant as it explores the connection between insulin signaling, metabolism, and memory, highlighting a systemic mechanism that could influence longevity and age-related cognitive functions.
Dandan Zong, Baihui Sun, Qiting Ye ...
· Aging cell
· Department of Endocrinology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
· pubmed
As global aging accelerates, the incidence of thyroid diseases, particularly hypothyroidism, is rising in the elderly. The thyroid-stimulating hormone (TSH) levels increase in healthy elderly populations. However, whether the thyroid undergoes cellular senescence and how this rel...
As global aging accelerates, the incidence of thyroid diseases, particularly hypothyroidism, is rising in the elderly. The thyroid-stimulating hormone (TSH) levels increase in healthy elderly populations. However, whether the thyroid undergoes cellular senescence and how this relates to thyroid hormone (TH) synthesis remain unclear. To investigate the molecular and functional characteristics of thyroid aging, we performed scRNA-seq on human thyroids from young, middle-aged, and old groups, identifying thousands of aging-related differentially expressed genes and revealing the early onset of aging in the middle-aged group. As aging progresses, the expression levels of genes related to TH synthesis increase, suggesting that epithelial cells (EPI) adjust their gene expression in response to elevated TSH levels. Additionally, the senescence-associated secretory phenotype (SASP) in EPI cells is progressively enhanced with aging. We identified a subgroup of epithelial cells (CDKN1A_EPI) characterized by reduced functionality and significantly elevated levels of cellular senescence. We found that the core circadian rhythm gene BMAL1 (ARNTL) is downregulated during aging. We further validated this finding using the thyroid-specific Bmal1 knockout mouse model, showing that the downregulation of Bmal1 inhibits the expression of Nfkbia (NF-κB inhibitor alpha), thereby accelerating cellular senescence and impairing hormone synthesis. Finally, through cell line experiments and transcriptome sequencing, we confirmed that BMAL1 knockout leads to decreased NFKBIA expression, promoting thyroid cellular senescence. Our study demonstrates that circadian rhythm disruption accelerates cellular senescence in the thyroid and exacerbates the decline of thyroid function, providing a novel theoretical foundation for understanding thyroid aging mechanisms and maintaining thyroid function stability.
Longevity Relevance Analysis
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The paper claims that downregulation of the circadian gene BMAL1 accelerates cellular senescence in the thyroid, impairing hormone synthesis. This research addresses the mechanisms of aging at the cellular level, specifically how circadian rhythms influence thyroid function and cellular senescence, which are critical aspects of longevity and age-related diseases.
Pushkal Sharma, Colin Y Kim, Heather R Keys ...
· Polyamines
· Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
· pubmed
Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutical...
Polyamines are abundant and evolutionarily conserved metabolites that are essential for life. Dietary polyamine supplementation extends life-span and health-span. Dysregulation of polyamine homeostasis is linked to Parkinson's disease and cancer, driving interest in therapeutically targeting this pathway. However, measuring cellular polyamine levels, which vary across cell types and states, remains challenging. We introduce a genetically encoded polyamine reporter for real-time measurement of polyamine concentrations in single living cells. This reporter utilizes the polyamine-responsive ribosomal frameshift motif from the OAZ1 gene. We demonstrate broad applicability of this approach and reveal dynamic changes in polyamine levels in response to genetic and pharmacological perturbations. Using this reporter, we conduct a genome-wide CRISPR screen and uncover an unexpected link between mitochondrial respiration and polyamine import, which are both risk factors for Parkinson's disease. By offering a lens to examine polyamine biology, this reporter may advance our understanding of these ubiquitous metabolites and accelerate therapy development.
Longevity Relevance Analysis
(4)
The paper claims to introduce a genetically encoded reporter that allows for real-time measurement of polyamine concentrations in living cells. This research is relevant as it explores the role of polyamines in cellular health and their potential link to age-related diseases, thereby addressing mechanisms that could influence longevity and health-span.
Anna Calabrò, Anna Aiello, Paula Silva ...
· GeroScience
· Laboratory of Immunopathology and Immunosenescence, Department of Biomedicine, Neurosciences and Advanced Diagnostics, University of Palermo, 90134, Palermo, Italy.
· pubmed
Geroprotectors are compounds that target the underlying mechanisms of ageing to delay the onset of age-related diseases and extend both lifespan and health span. As ageing is driven by the accumulation of cellular damage, DNA instability, epigenetic changes, mitochondrial dysfunc...
Geroprotectors are compounds that target the underlying mechanisms of ageing to delay the onset of age-related diseases and extend both lifespan and health span. As ageing is driven by the accumulation of cellular damage, DNA instability, epigenetic changes, mitochondrial dysfunction, and chronic inflammation, the concept of geroprotection focuses on compounds that can mitigate these processes. Oleuropein (OLE) and its derivative hydroxytyrosol (HT), both phenolic molecules derived from Olea europaea (olive tree), have gained significant attention as potential geroprotectors due to their potent antioxidant and anti-inflammatory properties. These phytochemicals, central to the Mediterranean diet, activate key molecular pathways such as nuclear factor erythroid 2-related factor 2, reducing oxidative stress and modulating inflammatory responses. Through these mechanisms, OLE and HT help counteract inflammageing, a critical factor in age-related dysfunction. This review highlights the role of OLE and HT as geroprotective agents, emphasising their ability to target the hallmarks of ageing and their potential to improve health span by slowing the progression of age-related conditions. With proven efficacy in various biological models, these compounds represent promising tools in the ongoing search for strategies to enhance the quality of life in ageing populations.
Longevity Relevance Analysis
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Oleuropein and hydroxytyrosol may serve as geroprotective agents by targeting the hallmarks of ageing. The paper discusses compounds that address the underlying mechanisms of ageing, which aligns with the goals of longevity research.
Xinying Wang, Limin Song, Jingwen Zhao ...
· Journal of materials chemistry. B
· National Engineering Research Center for Biomaterials, College of Biomedical Engineering, Sichuan University, Chengdu, 610064, P. R. China. [email protected].
· pubmed
During tissue repair, stress-induced cellular senescence represents a critical factor that impedes the regenerative potential of tissues. While the regulatory effects of matrix viscoelasticity on cellular behavior have been documented, their role and correlated mechanisms underly...
During tissue repair, stress-induced cellular senescence represents a critical factor that impedes the regenerative potential of tissues. While the regulatory effects of matrix viscoelasticity on cellular behavior have been documented, their role and correlated mechanisms underlying cellular senescence remain unclear. In this study, we engineered a viscoelastic gel matrix exhibiting a storage modulus of approximately 3 kPa, with a tunable loss modulus ranging from 0 to 300 Pa by incorporating linear alginate and modulating the compactness of a polyacrylamide-based covalent network. Utilizing a UV-induced senescence model, we observed that increasing the matrix's viscoelasticity from 0 Pa to 300 Pa led to a significant reduction in the proportion of senescent cells, from 90.5% to 22.7%. Furthermore, cells cultured in these matrices exhibited a tendency to form cell aggregation, with the cell populations demonstrating a collective resistance to stresses. This indicated that viscoelastic materials would promote enhanced cellular interactions, thereby strengthening cellular resilience against UV-induced stresses. Furthermore, combined with microarray analysis, it was concluded that the presence of viscoelastic components activated the connexin 43 (Cx43)-modulated gap junction for cluster formation, thereby suppressing the senescence-associated signaling pathways, including Wnt/β-catenin, MAPK, NF-κB, and TGF-β. Additionally, the integrin-cytoskeleton-Yes-associated protein (YAP) signaling axis played an active role in delaying cell aging. These results provide novel insights into the regulatory role of viscoelastic materials in cellular senescence and offer a compelling foundation for the development of advanced biomaterials for tissue repair.
Longevity Relevance Analysis
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The paper claims that increasing the viscoelasticity of a matrix significantly reduces cellular senescence and promotes cell aggregation. This research is relevant as it addresses mechanisms that could potentially counteract cellular senescence, a key factor in aging and age-related decline.
Graham, Z. A., Bubak, M. P., Raymond-Pope, C. J. ...
· geriatric medicine
· Florida Institute for Human and Machine Cognition
· medrxiv
Age-related functional declines are thought to be caused by hallmark biological processes that manifest in physical, mental, and metabolic impairments compromising intrinsic capacity, healthspan and quality-of-life. Exercise is a multipotent treatment with promise to mitigate mos...
Age-related functional declines are thought to be caused by hallmark biological processes that manifest in physical, mental, and metabolic impairments compromising intrinsic capacity, healthspan and quality-of-life. Exercise is a multipotent treatment with promise to mitigate most aging hallmarks, but there is substantial variability in individual exercise responsiveness. This inter-individual response heterogeneity (IRH) was first extensively interrogated by Bouchard and colleagues in the context of endurance training. Our group has interrogated IRH in response to resistance training and combined training, and we have conducted trials in older adults examining dose titration and adjuvant treatments in attempts to boost response rates. Despite the work of many groups, the mechanisms underpinning IRH and effective mitigation strategies largely remain elusive. The National Institute on Aging (NIA) hosted a focused workshop in 2022 titled Understanding heterogeneity of responses to, and optimizing clinical efficacy of, exercise training in old adults. This workshop spurred a dedicated NIA request for applications (RFA) with the major goal to better understand factors underlying response variability to exercise training in older adults. We developed a two-phase Sequential Multiple Assignment Randomized Trial (SMART) in response to the RFA that will allow us to classify individual responsiveness to combined endurance and resistance training and interrogate potential mechanistic underpinnings (Phase I), followed by an approach to boost responsiveness (Phase II). Using deep in vivo, ex vivo, and molecular phenotyping, we will establish multidimensional biocircuitry of responsiveness and build predictive models, providing a basis for personalized exercise prescriptions.
Longevity Relevance Analysis
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The paper claims to develop a multidimensional modeling approach to classify individual responsiveness to exercise training in older adults. This research is relevant as it aims to understand and optimize exercise interventions that could mitigate age-related functional declines, addressing the root causes of aging rather than merely treating symptoms.
Koitz, F. A., Miller, C. P., Gordon, K. L.
· developmental biology
· The University of North Carolina at Chapel Hill
· biorxiv
Early life stresses impact reproductive outcomes in many organisms. In response to crowding and starvation, C. elegans nematodes form dauer larvae, in which development arrests until conditions improve. We discovered dramatic differences in gonad size and germ cell number among d...
Early life stresses impact reproductive outcomes in many organisms. In response to crowding and starvation, C. elegans nematodes form dauer larvae, in which development arrests until conditions improve. We discovered dramatic differences in gonad size and germ cell number among dauers that form under different conditions. We used live cell imaging of fluorescent markers in otherwise wild-type and mutant animals combined with food-removal, recovery, and brood-size assays to investigate the causes and consequences of this germline difference. Pre-dauer feeding, but not nutrient sensing via the DAF-2/insulin-like signaling receptor or DAF-7/TGF-{beta}, is required for plasticity in gonad size. Gonad differences in dauer have lifelong reproductive consequences; worms with small dauer gonads recover to have smaller broods. Somatic and germline development are decoupled as pre-dauer starvation induces germline quiescence while the soma continues its development until dauer is formed. A rapid return to germline Notch-dependence and an increase in presentation by the germline stem cell niche of the Notch ligand LAG-2--regulated at the protein and not transcript level--are among the earliest events of dauer recovery.
Longevity Relevance Analysis
(4)
Pre-dauer starvation affects gonad size and germ cell number in C. elegans, leading to lifelong reproductive consequences. The study explores how early life stresses can influence reproductive outcomes, which is relevant to understanding mechanisms of aging and longevity.
Yao Zhang, Peng Ma, Saifei Wang ...
· Autophagy
· Yangzhi Rehabilitation Hospital, Sunshine Rehabilitation Center, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 20092, China.
· pubmed
Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa
Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa
Longevity Relevance Analysis
(4)
Restoring calcium crosstalk between the endoplasmic reticulum and mitochondria rejuvenates intestinal stem cells through autophagy in aged Drosophila. This research addresses a fundamental aspect of cellular aging by exploring mechanisms that could potentially reverse age-related decline in stem cell function.
Klara Kohoutova, Pavel Srb, Veronika Obsilova ...
· Tumor Suppressor Protein p53
· Department of Physical and Macromolecular Chemistry, Faculty of Science, Charles University, Prague, Czech Republic.
· pubmed
The transcription factors FOXO4 and p53 regulate aging, and their deregulation has been linked to several diseases, including cancer. Under stress conditions, cellular senescence is promoted by p53 sequestration and senescence-associated protein p21 transcriptional upregulation i...
The transcription factors FOXO4 and p53 regulate aging, and their deregulation has been linked to several diseases, including cancer. Under stress conditions, cellular senescence is promoted by p53 sequestration and senescence-associated protein p21 transcriptional upregulation induced by interactions between the FOXO4 Forkhead DNA-binding domain and the p53 transactivation domain. However, the molecular details of these interactions remain unclear. Here, we report that these interactions between p53 and FOXO4 domains are highly heterogeneous. The p53 transactivation domain primarily interacts with the region formed by the N-terminal helical bundle of the FOXO4 Forkhead domain but retains a substantial degree of flexibility in the complex. In addition, NMR data-driven molecular simulations suggest that p53 interacts with FOXO4 through multiple binding modes. Overall, our findings not only provide the structural insights into interactions between FOXO4 and p53 but also highlight their potential as targets for developing senolytic compounds.
Longevity Relevance Analysis
(4)
The paper claims that the interactions between FOXO4 and p53 are heterogeneous and provide structural insights that could inform the development of senolytic compounds. This research is relevant as it explores the molecular mechanisms underlying aging and cellular senescence, which are central to understanding and potentially mitigating age-related diseases.
Matias Fuentealba, Dobri Kiprov, Kevin Schneider ...
· Aging cell
· Buck Institute for Research on Aging, Novato, California, USA.
· pubmed
We conducted a randomized, placebo-controlled trial to assess the safety and biological age (BA) effects of various therapeutic plasma exchange (TPE) regimens in healthy adults over 50. Participants received bi-weekly TPE with or without intravenous immunoglobulin (IVIG), monthly...
We conducted a randomized, placebo-controlled trial to assess the safety and biological age (BA) effects of various therapeutic plasma exchange (TPE) regimens in healthy adults over 50. Participants received bi-weekly TPE with or without intravenous immunoglobulin (IVIG), monthly TPE, or placebo. Randomization was based on entry date, and treatments were blinded to maintain objectivity. Primary objectives were to assess long-term TPE safety and changes in biological clocks. Secondary goals included identifying optimal regimens. Exploratory analyses profiled baseline clinical features and longitudinal changes across the epigenome, proteome, metabolome, glycome, immune cytokines, iAge, and immune cell composition. We demonstrate in 42 individuals randomized to various treatment arms or placebo that long-term TPE was found to be safe, with only two adverse events requiring discontinuation and one related to IVIG. TPE significantly improved biological age markers, with 15 epigenetic clocks showing rejuvenation compared to placebo (FDR < 0.05). Biweekly TPE combined with intravenous immunoglobulin (TPE-IVIG) proved most effective, inducing coordinated cellular and molecular responses, reversing age-related immune decline, and modulating proteins linked to chronic inflammation. Integrative analysis identified baseline biomarkers predictive of positive outcomes, suggesting TPE-IVIG is particularly beneficial for individuals with poorer initial health status. This is the first multi-omics study to examine various TPE modalities to slow epigenetic biologic clocks, which demonstrate biological age rejuvenation and the molecular features associated with this rejuvenation. Trial Registration: Registered trial NCT06534450 on clinicaltrials.gov under the purview of the Diagnostic Investigational Review Board.
Longevity Relevance Analysis
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Therapeutic plasma exchange (TPE) can rejuvenate biological age markers in healthy adults over 50. This study addresses biological age rejuvenation, which is directly related to the root causes of aging and has implications for lifespan extension and age-related health improvements.
Allavena, G., Rossiello, F., Idilli, A. I. ...
· pathology
· Institute for Research on Cancer and Aging of Nice (IRCAN)
· biorxiv
Telomerase activity is restricted in somatic cells, resulting in progressive telomere shortening. Telomere erosion eventually activates the DNA damage response (DDR), inducing cell-cycle arrest and cellular senescence or apoptosis. We previously reported that telomere dysfunction...
Telomerase activity is restricted in somatic cells, resulting in progressive telomere shortening. Telomere erosion eventually activates the DNA damage response (DDR), inducing cell-cycle arrest and cellular senescence or apoptosis. We previously reported that telomere dysfunction induces the transcription of telomeric non-coding RNAs (tncRNAs) which are critical mediators of DDR activation. Blocking tncRNAs with telomeric antisense oligonucleotides (tASOs) suppresses in vivo DDR signaling and its downstream effects. Here, we show that tASO-mediated inhibition of telomeric DDR in second-generation tert-/- zebrafish embryos with critically short telomeres leads to improved developmental outcomes and rescues premature aging phenotypes, including enhanced survival. Notably, a single tASO treatment administered at the one-cell stage of first-generation tert-/- embryos leads to enhanced fertility observed in 6-month-old adults. Overall, these findings demonstrate that tASO-based inhibition of telomeric DDR is sufficient to effectively rescue premature aging phenotypes in zebrafish.
Longevity Relevance Analysis
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The paper claims that telomeric antisense oligonucleotides can inhibit the DNA damage response and rescue premature aging phenotypes in zebrafish. This research addresses the root causes of aging by targeting telomere dysfunction, which is a significant factor in the aging process.
Vivas, O., Baudot, M., Choi, S. ...
· biophysics
· University of Washington
· biorxiv
Every heartbeat is initiated by a spontaneous electrical signal generated inside the cardiac pacemaker. The generation of this electrical signal depends on the coordinated opening and closing of different ion channels, where voltage-gated L-type calcium channels play a central ro...
Every heartbeat is initiated by a spontaneous electrical signal generated inside the cardiac pacemaker. The generation of this electrical signal depends on the coordinated opening and closing of different ion channels, where voltage-gated L-type calcium channels play a central role. Despite the reliability of the pacemaker, all mammals experience a linear slowdown of the pacemaker rate with age. In humans, this slowing can become pathological and constitutes the main cause for the requirement of the implantation of artificial pacemakers. However, the mechanisms behind the age-associated slowdown of the pacemaker are not well understood. Here, we show that age alters L-type calcium channels in pacemaker cells from mice. The age-associated alterations include: i) a reduction in the density of the channels at the plasma membrane, ii) a reduction in the clustering of the channels, and iii) a decrease in channel open probability. Altogether, these age-associated alterations result in a global reduction of the L-type calcium current density and in a slowdown of the pacemaker diastolic depolarization. Remarkably, increasing the open probability of L-type calcium channels pharmacologically was enough to restore pacemaker rate in old cells to the same levels observed in the young. Overall, our findings provide evidence that proper organization and function of L-type calcium channels is impaired by aging and that this dysfunction contributes to the slowdown of pacemaker cells in old animals.
Longevity Relevance Analysis
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Aging impairs the organization and function of L-type calcium channels in cardiac pacemaker cells, contributing to the slowdown of the pacemaker rate. This paper is relevant as it addresses a mechanistic understanding of how aging affects cardiac function, which is a critical aspect of longevity and age-related health.
Natalia Jarzebska, Stefan R Bornstein, Sergey Tselmin ...
· Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme
· Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
· pubmed
Human aging is intrinsically associated with the onset and the progression of several disease states causing significant disability and poor quality of life. Although such association was traditionally considered immutable, recent advances have led to a better understanding of se...
Human aging is intrinsically associated with the onset and the progression of several disease states causing significant disability and poor quality of life. Although such association was traditionally considered immutable, recent advances have led to a better understanding of several critical biochemical pathways involved in the aging process. This, in turn, has stimulated a significant body of research to investigate whether reprogramming these pathways could delay the progression of human ageing and/or prevent relevant disease states, ultimately favoring healthier aging process. Cellular senescence is regarded as the principal causative factor implicated in biological and pathophysiological processes involved in aging. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and an independent risk factor for several age-associated diseases. The selective extracorporeal removal of ADMA is emerging as a promising strategy to reduce the burden of age-associated disease states. This article discusses the current knowledge regarding the critical pathways involved in human aging and associated diseases and the possible role of ADMA as a target for therapies leading to healthier aging processes.
Longevity Relevance Analysis
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The paper discusses the potential of targeting asymmetric dimethylarginine (ADMA) to influence aging processes and reduce age-associated diseases. This research is relevant as it explores a biochemical pathway that could contribute to healthier aging, rather than merely addressing symptoms of age-related diseases.
Woldhuis, R. R., Bekker, N. J., Nijnatten, J. L. L. ...
· pathology
· Department of Pathology and Medical Biology, Groningen Research Institute for Asthma and COPD (GRIAC), University of Groningen, University Medical Centre Gronin
· biorxiv
Rationale: Higher levels of senescence have been demonstrated in COPD patients, including severe early onset (SEO)-COPD. Recently we demonstrated a link between senescence and extracellular matrix (ECM) dysregulation in lung fibroblasts. Whether this in vitro observation also tra...
Rationale: Higher levels of senescence have been demonstrated in COPD patients, including severe early onset (SEO)-COPD. Recently we demonstrated a link between senescence and extracellular matrix (ECM) dysregulation in lung fibroblasts. Whether this in vitro observation also translates in vivo has not been shown yet. Objectives: To determine whether senescence can contribute to COPD-associated ECM-related changes in lung tissue. Methods: Transcriptomics and proteomics analyses were performed on lung tissue from 60 COPD patients (including 18 SEO-COPD patients) and 32 controls. Expression levels of 471 ECM-related genes and proteins were compared between (SEO-)COPD and controls. Differentially expressed ECM-related genes and proteins were then correlated with six major senescence markers. ECM-senescence correlations were validated in primary human lung fibroblasts in vitro. Results: We identified 12 COPD- and 57 SEO-COPD-associated ECM-related genes and 4 COPD- and 9 SEO-COPD-associated ECM-related proteins. More than half (36 out of 68 unique genes) of the (SEO-)COPD-associated ECM-related proteins were significantly correlated with one or more senescence markers at transcript level, with the most and strongest correlations with p21 (26 genes). The correlation of 3 ECM-related genes with p21 was validated in primary lung fibroblasts cultured at baseline and ADAMTS1 was increased in senescence-induced lung fibroblasts. Conclusions: Many of the (SEO-)COPD-associated ECM-related changes in lung tissue were correlated with the senescence marker p21. As many of these ECM-related proteins are involved in ECM organization and include proteases, these results indicate a role for cellular senescence in disturbed ECM organization and protease-antiprotease imbalance in COPD.
Longevity Relevance Analysis
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The paper claims that cellular senescence contributes to ECM-related changes in lung tissue in COPD patients. The study addresses the role of cellular senescence, a key aspect of aging, in the pathophysiology of COPD, linking it to extracellular matrix dysregulation, which is relevant to understanding age-related diseases.
Jung Min Hwang, Soo Hyun Lee, Eun Jae Baek ...
· Skin Aging
· Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea.
· pubmed
Skin ageing is a complex and multifaceted biological process that involves the accumulation of senescent dermal fibroblasts. While fractional microneedle radiofrequency (MNRF) is widely used for skin rejuvenation, the underlying molecular mechanisms are unknown. This study aimed ...
Skin ageing is a complex and multifaceted biological process that involves the accumulation of senescent dermal fibroblasts. While fractional microneedle radiofrequency (MNRF) is widely used for skin rejuvenation, the underlying molecular mechanisms are unknown. This study aimed to investigate the efficacy of fractional MNRF in altering the cellular milieu of aged skin and to evaluate clinical skin improvements. Thirty female volunteers aged ≥ 60 years with visible periorbital wrinkles received four consecutive treatments of either microneedling or MNRF on randomly assigned facial sides. Based on biophysical measurements, MNRF treatment improved wrinkles, elasticity, hydration, and transepidermal water loss compared to baseline. Histological analysis revealed that the MNRF-treated sides exhibited increased proliferation of non-senescent fibroblasts, a reduced number of senescent fibroblasts, and elevated collagen and elastin levels, compared to the MN-treated sides. In additional analyses, differences in collagen density and hydration between the two sides of the face were statistically significant only in subjects with a marked reduction in senescent fibroblasts in MNRF-treated sides. Our data suggest that, compared to MN, MNRF induces greater clinical and histological improvements in aged skin, likely by altering the dermal fibroblast milieu through the dual effect of eliminating senescent fibroblasts and increasing the number of non-senescent fibroblasts.
Longevity Relevance Analysis
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Fractional microneedle radiofrequency treatment improves the fibroblast milieu in aged skin by reducing senescent fibroblasts and increasing non-senescent fibroblasts. This study addresses the cellular mechanisms underlying skin aging, which is a fundamental aspect of longevity research.
Shu, J., Guo, Y., Chirinos, J. ...
· genetic and genomic medicine
· University of Pennsylvania
· medrxiv
Organ-specific aging clocks have shown promise as predictors of disease risk and aging trajectories; however, the underlying biological mechanisms they reflect remain largely unexplored. Here, we use large-scale proteomic and imaging data to investigate the relationships among or...
Organ-specific aging clocks have shown promise as predictors of disease risk and aging trajectories; however, the underlying biological mechanisms they reflect remain largely unexplored. Here, we use large-scale proteomic and imaging data to investigate the relationships among organ-specific and modality-specific aging clocks and to uncover the biological processes they represent. By estimating paired protein-based and imaging-based aging clocks across 8 major organs, we demonstrate that these omics and structural profiles exhibit distinct phenotypic and genetic signatures, each potentially quantifying different stages and playing complementary roles within a unified biological aging process. Furthermore, context-specific aging clocks from multiple organs often converge and jointly capture established biological and disease pathways. For example, 65.7% of the KEGG Alzheimer's disease pathway is enriched by at least one of 11 protein- and imaging-based aging clocks, with each clock representing different components of the pathway. These results underscore the importance of a pan-organ multi-modal perspective for quantifying the mechanisms underlying age-related diseases. Additionally, we identify modality-specific links between aging clocks and complex diseases and lifestyle factors. In summary, we uncover intricate relationships among molecular and structural aging clocks across human organs, providing novel insights into their context-specific roles in capturing consequences of aging biology and their implications for disease risk.
Longevity Relevance Analysis
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The paper claims that organ-specific and modality-specific aging clocks can reveal distinct biological processes and their roles in age-related diseases. This research is relevant as it explores the underlying biological mechanisms of aging across multiple organs, contributing to a deeper understanding of the root causes of aging and potential interventions.
Yan Pan, Hongxia Cai, Fang Ye ...
· Aging cell
· Department of Neurology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
· pubmed
Despite the growing interest in developing anti-aging drugs, high costs and low success rates of traditional drug discovery methods pose significant challenges. Aging is a complex biological process associated with numerous diseases, making the identification of compounds that ca...
Despite the growing interest in developing anti-aging drugs, high costs and low success rates of traditional drug discovery methods pose significant challenges. Aging is a complex biological process associated with numerous diseases, making the identification of compounds that can modulate aging mechanisms critically important. Accelerating the discovery of potential anti-aging compounds is essential to overcome these barriers and enhance lifespan and healthspan. Here, we present ElixirSeeker, a machine learning framework designed to maximize feature capture of lifespan-extending compounds through multi-fingerprint fusion mechanisms. Utilizing this approach, we identified several promising candidate drugs from external compound databases. We tested the top six hits in Caenorhabditis elegans and found that four of these compounds-including Praeruptorin C, Polyphyllin VI, Thymoquinone, and Medrysone-extended the organism's lifespan. This study demonstrates that ElixirSeeker effectively accelerates the identification of viable anti-aging compounds, potentially reducing costs and increasing the success rate of drug development in this field.
Longevity Relevance Analysis
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The paper claims that the ElixirSeeker framework can identify compounds that extend lifespan in Caenorhabditis elegans. This research is relevant as it focuses on discovering compounds that can potentially modulate aging mechanisms, directly addressing the root causes of aging rather than merely treating age-related diseases.
Sibin Nambidi, Sneha Pallatt, Antara Banerjee ...
· Neoplasms
· Department of Medical Biotechnology, Faculty of Allied Health Sciences, Chettinad Academy of Research and Education (CARE), Chettinad Hospital and Research Institute (CHRI), Chennai, Tamil Nadu, India.
· pubmed
Klotho, named after the youngest of the three Fates in Greek mythology daughters of Zeus and Nyx, who together spin the thread of life, allot destiny, and determine the time of passing for both mortals and immortals, is an important regulatory factor in aging and cancer dynamics....
Klotho, named after the youngest of the three Fates in Greek mythology daughters of Zeus and Nyx, who together spin the thread of life, allot destiny, and determine the time of passing for both mortals and immortals, is an important regulatory factor in aging and cancer dynamics. Initially described as an aging-suppressing protein, Klotho is now recognized for its more diverse role in modulating key signaling pathways like Wnt/β-catenin, IGF-1, PI3K/AKT, and TGF-β. Essentially, its various pro-cellular health functions, such as antioxidant, anti-inflammatory, and tumor-suppressive activities, are, in fact, considered that ensures the maintenance of cellular health and reduce complications related to aging. Klotho deficiency is associated with accelerated aging, chronic kidney disease, cardiovascular disorders, neurodegeneration, and various cancers. This review thus covers the twin roles of Klotho as an antiaging and tumor-suppressor protein, on their therapeutic potential, as well as advances in delivery systems and development of biomarkers and challenges for clinical translation.. Moreover, natural strategies like exercise and dietary interventions are explored that could help overcome Klotho deficiency. Further research with Klotho may offer a paradigm shift in the treatment of aging and cancer and add yet another avenue to increase survival of the patients.
Longevity Relevance Analysis
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Klotho protein plays a dual role as an antiaging and tumor-suppressor protein, with potential therapeutic implications for aging and cancer. The paper discusses mechanisms that could address the root causes of aging and proposes strategies to mitigate Klotho deficiency, aligning with longevity research goals.
Noureen, N., Kang, M. H.
· bioinformatics
· Texas Tech University Health Sciences Center
· biorxiv
Telomerase activity plays a critical role in tumor growth and is quantified based on its level of expression. However, how these levels are associated with different pathways across various cancer types remains elusive due to the lack of a classification schema. Here, we defined ...
Telomerase activity plays a critical role in tumor growth and is quantified based on its level of expression. However, how these levels are associated with different pathways across various cancer types remains elusive due to the lack of a classification schema. Here, we defined an unsupervised learning metric for the quantitative measurement of telomerase activity and robustly classified the samples into low and high telomerase groups across different cancers. Using this classification system, we analyzed the data for over 9000 bulk tumors, single cells, and spatially organized tissues, and we found that telomerase high groups across the majority of cancers are strongly associated with genomic instability. On the contrary, lower group of telomerase across various cancers are significantly associated with cellular senescence, inflammation, ROS, and MAPK pathway activities. Cellular senescence, a hallmark of cellular aging, was dominant in older adults over the high telomerase levels in the majority of cancers, normal tissues, and human development phases. Our study comprehensively illustrates that lower levels of telomerase are associated with senescence-phenotype in the majority of cancers, which is strongly favorable for better survival outcomes.
Longevity Relevance Analysis
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Lower levels of telomerase are associated with cellular senescence and better survival outcomes in cancer patients. The study connects telomerase activity with cellular senescence, a hallmark of aging, suggesting insights into the aging process and its implications for longevity.
Yu Zhang, Xiaojie Liu, Hairong Lian ...
· Aging cell
· College of Marine Science and Engineering, Nanjing Normal University, Nanjing, Jiangsu, People's Republic of China.
· pubmed
Metformin, a medication primarily used to treat diabetes, has gained attentions for its potential antiaging properties. Although the metabolic and cellular pathways behind its longevity effects have been widely studied, few studies have explored the epigenetic regulatory effects ...
Metformin, a medication primarily used to treat diabetes, has gained attentions for its potential antiaging properties. Although the metabolic and cellular pathways behind its longevity effects have been widely studied, few studies have explored the epigenetic regulatory effects of metformin, which are a crucial factor in aging processes. In this study, we examined the antiaging effects of metformin using the Brachionus rotifer as a model, focusing on the regulation of mRNA N6-methyladenosine (m6A), a key RNA modification involved in mRNA stability, translation, and splicing. We found metformin significantly extended the rotifers' lifespan, mimicking the effects of dietary restriction (DR), a well-established antiaging intervention. Both metformin and DR modulate m6A dynamics, with a notable reduction in the m6A modification of MTR (5-methyltetrahydrofolate-homocysteine methyltransferase). This reduction led to decreased MTR expression and lowered levels of S-adenosylmethionine (SAM), a critical metabolite in the one-carbon cycle. We propose that the downregulation of MTR through m6A modification limits methionine synthesis and imposes methionine restriction, a key factor in promoting longevity. Our findings reveal a novel epitranscriptional regulatory model by which metformin and DR modulate m6A to extend lifespan, highlighting MTR as a central regulator of aging and suggesting potential therapeutic strategies for healthy aging through m6A and methionine metabolism.
Longevity Relevance Analysis
(4)
Metformin and dietary restriction extend lifespan in Brachionus rotifers by reducing m6A-dependent stabilization of methionine synthase mRNA. This study addresses the underlying mechanisms of aging by exploring epigenetic regulation and metabolic pathways, contributing to the understanding of longevity interventions.
Filippos Anagnostakis, Sarah Ko, Mehrshad Saadatinia ...
· Metabolome
· Laboratory of AI and Biomedical Science (LABS), Columbia University, New York, NY, USA.
· pubmed
Multi-organ biological aging clocks across different organ systems have been shown to predict human disease and mortality. Here, we extend this multi-organ framework to plasma metabolomics, developing five organ-specific metabolome-based biological age gaps (MetBAGs) using 107 pl...
Multi-organ biological aging clocks across different organ systems have been shown to predict human disease and mortality. Here, we extend this multi-organ framework to plasma metabolomics, developing five organ-specific metabolome-based biological age gaps (MetBAGs) using 107 plasma non-derivatized metabolites from 274,247 UK Biobank participants. Our age prediction models achieve a mean absolute error of approximately 6 years (0.25
Longevity Relevance Analysis
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The paper claims to develop organ-specific metabolome-based biological age gaps that predict cardiometabolic conditions and mortality risk. This research is relevant as it addresses biological aging through metabolomics, potentially offering insights into the root causes of aging and age-related diseases.
Abhishek Vats, Yibo Xi, Amanda S Wolf-Johnston ...
· Guanine
· Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
· pubmed
Vision decline in the elderly, often due to retinal aging, predisposes individuals to pathologies like age-related macular degeneration. Currently, there are few effective oral treatments for this condition. Our study introduces an oral agent, 8-aminoguanine (8-AG), which targets...
Vision decline in the elderly, often due to retinal aging, predisposes individuals to pathologies like age-related macular degeneration. Currently, there are few effective oral treatments for this condition. Our study introduces an oral agent, 8-aminoguanine (8-AG), which targets age-related retinal degeneration using an aged Fischer 344 rat model. When administered in drinking water at a low dose for 8 weeks starting at 22 months of age, 8-AG significantly preserves retinal structure and function, as evidenced by increased retinal thickness, enhanced photoreceptor integrity, and improved electroretinogram responses. 8-AG reduces apoptosis, oxidative damage, and microglial/macrophage activation in aging retinae. 8-AG also mitigates retinal inflammation at transcriptional and cytokine levels. Extending treatment to 17 weeks further amplifies these protective effects. Given its efficacy in various disease models, 8-AG shows great promise as an anti-aging compound with the potential to mitigate common hallmarks of aging.
Longevity Relevance Analysis
(4)
Oral administration of 8-aminoguanine significantly preserves retinal structure and function in an aged rat model. The study addresses a potential therapeutic approach to mitigate age-related retinal degeneration, which is a direct concern of aging and its associated pathologies.
Arun Balachandran, Heming Pei, Yifan Shi ...
· Nature aging
· Robert N Butler Columbia Aging Center, Columbia University Mailman School of Public Health, New York, NY, USA.
· pubmed
As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy do not distinguish differences caused by early-life factors, like prenatal care and nut...
As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy do not distinguish differences caused by early-life factors, like prenatal care and nutrition, from those caused by ongoing changes in people's bodies that are due to aging and that may be modifiable. Here we introduce an adapted Pace of Aging method designed to quantify differences between individuals and populations in the speed of aging-related health declines. The adapted Pace of Aging method, implemented in parallel in data from the US Health and Retirement Study and in the English Longitudinal Study of Aging (combined n = 19,045), integrates longitudinal data on blood biomarkers, physical measurements and functional tests. It reveals stark differences in rates of aging between population subgroups and demonstrates strong and consistent prospective associations with incident morbidity, disability and mortality. This adapted and generalizable method to measure Pace of Aging can advance the population science of healthy longevity.
Longevity Relevance Analysis
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The paper introduces an adapted Pace of Aging method to quantify differences in aging-related health declines among older adults. This research is relevant as it seeks to understand and potentially modify the pace of aging, which is central to improving healthspan and longevity.
Nicholas Riccardi, Alex Teghipco, Sarah Newman-Norlund ...
· Aging
· Department of Communication Sciences and Disorders, University of South Carolina, Columbia, SC, USA. [email protected].
· pubmed
'Brain age' is a biological clock typically used to describe brain health with one number, but its relationship with established gradients of cortical organization remains unclear. We address this gap by leveraging a data-driven, region-specific brain age approach in 335 neurolog...
'Brain age' is a biological clock typically used to describe brain health with one number, but its relationship with established gradients of cortical organization remains unclear. We address this gap by leveraging a data-driven, region-specific brain age approach in 335 neurologically intact adults, using a convolutional neural network (volBrain) to estimate regional brain ages directly from structural MRI without a predefined set of morphometric properties. Six distinct gradients of brain aging are replicated in two independent cohorts. Spatial patterns of accelerated brain aging in older adults quantitatively align with the archetypal sensorimotor-to-association axis of cortical organization. Other brain aging gradients reflect neurobiological hierarchies such as gene expression and externopyramidization. Participant-level correspondences to brain age gradients are associated with cognitive and sensorimotor performance and explained behavioral variance more effectively than global brain age. These results suggest that regional brain age patterns reflect fundamental principles of cortical organization and behavior.
Longevity Relevance Analysis
(5)
Distinct brain age gradients reflect neurobiological hierarchies that correlate with cognitive and sensorimotor performance. The study's focus on regional brain aging patterns and their association with cognitive function provides insights into the underlying mechanisms of brain health and aging, which are crucial for understanding longevity.
Schurman, C. A., Bons, J., Kumaar, P. V. ...
· cell biology
· Buck Institute for Research on Aging
· biorxiv
Mass spectrometry imaging (MSI) is a rapidly advancing technology that provides mapping of the spatial molecular landscape of tissues for a variety of analytes. Matrix-assisted laser desorption/ionization (MALDI)-MSI is commonly employed, however, confident in situ identification...
Mass spectrometry imaging (MSI) is a rapidly advancing technology that provides mapping of the spatial molecular landscape of tissues for a variety of analytes. Matrix-assisted laser desorption/ionization (MALDI)-MSI is commonly employed, however, confident in situ identification and accurate quantification of analytes remain challenging. We present a novel imaging methodology combining trapped ion mobility spectrometry (TIMS)-based parallel accumulation-serial fragmentation (PASEF) with MALDI ionization for targeted imaging parallel reaction monitoring (iprm-PASEF). We investigated the spatial distribution of lipids and metabolites in liver tissues from wild-type and CD38 knockout mice (CD38-/-). CD38, an enzyme involved in nicotinamide adenine dinucleotide (NAD) metabolism, significantly influences liver metabolic function and contributes to age-related NAD decline. Although CD38 deletion previously was linked to improved metabolic phenotypes, the underlying spatial metabolic mechanisms are poorly understood. The spatial iprm-PASEF workflow enabled confident identification and differentiation of lipid isomers at the MS2 fragment ion level and revealed increased NAD+ and decreased adenosine diphosphate ribose (ADPR), a by-product of NAD+ hydrolysis, in CD38-/- livers. This approach provided confident, specific, and robust MS2-based identification and quantification of fragment ions in spatial MSI experiments. Additionally, the innovative iprm-PASEF opens unprecedented opportunities for spatial metabolomics and lipidomics, offering spatially resolved insights into molecular mechanisms.
Longevity Relevance Analysis
(5)
The paper claims that CD38 knockout mice exhibit improved metabolic profiles due to altered spatial distributions of lipids and NAD+ metabolites. This research is relevant as it investigates the role of CD38 in NAD metabolism, which is linked to age-related metabolic decline, potentially addressing mechanisms underlying aging.
Aitor Picos, Nuria Seoane, Manuel Campos-Toimil ...
· Aging
· Physiology and Pharmacology of Chronic Diseases (FIFAEC), Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela, 15782, Santiago de Compostela, Spain. [email protected].
· pubmed
The aging vasculature is characterized by endothelial dysfunction, arterial stiffness, and increased susceptibility to vascular pathologies. Central to these changes is the process of cellular senescence, where endothelial and vascular smooth muscle cells lose their replicative a...
The aging vasculature is characterized by endothelial dysfunction, arterial stiffness, and increased susceptibility to vascular pathologies. Central to these changes is the process of cellular senescence, where endothelial and vascular smooth muscle cells lose their replicative and functional capacity and adopt a pro-inflammatory secretory phenotype. This review provides an overview of the key mechanisms underlying vascular senescence, including the p53/p21 and p16/Rb pathways, the senescence-associated secretory phenotype (SASP), and oxidative stress, examines its contribution to cardiovascular diseases in older adults, and highlights emerging therapeutic strategies aimed at delaying or reversing these age-related vascular changes. In vascular cells, DNA damage, oxidative stress, and chronic inflammation associated with aging converge to amplify senescence. Clinically, vascular senescence is linked with hypertension, atherosclerosis, and increased overall cardiovascular risk. Several interventions, ranging from senolytics to lifestyle factors, show promise in mitigating these changes; however, long-term studies are needed. Given that vascular senescence is a pivotal driver of cardiovascular pathology in aging, targeting senescent cells or their secretory phenotype may potentially offer new avenues for preventing or attenuating age-related vascular diseases. This review presents an updated and integrative overview of vascular senescence, connecting fundamental cellular mechanisms with their clinical manifestations and highlighting the most promising therapeutic interventions.
Longevity Relevance Analysis
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Targeting vascular senescence may offer new therapeutic strategies for preventing or attenuating age-related vascular diseases. The paper addresses the underlying mechanisms of vascular aging and senescence, which are critical to understanding and potentially mitigating the root causes of age-related diseases.
Saswat Kumar Mohanty, Vikas Kumar Sahu, Bhanu Pratap Singh ...
· Renal Insufficiency, Chronic
· Department of Biochemistry and Molecular Biology, Pondicherry University, Pondicherry, 605 014, India. [email protected].
· pubmed
Chronic kidney disease (CKD) is a global health challenge marked by progressive renal decline and increased mortality. The interplay between CKD and hypothyroidism, particularly nonthyroidal low-triiodothyronine (T3) syndrome, exacerbates disease progression, driven by HPT axis d...
Chronic kidney disease (CKD) is a global health challenge marked by progressive renal decline and increased mortality. The interplay between CKD and hypothyroidism, particularly nonthyroidal low-triiodothyronine (T3) syndrome, exacerbates disease progression, driven by HPT axis dysfunction and reduced Klotho levels due to the Wnt/β-catenin pathway activation. This study explored Klotho as a link between CKD and hypothyroidism using an adenine-induced CKD aged mouse model. Exogenous T3 and baicalein (BAI), targeting the Wnt pathway, were used to upregulate Klotho expression. Combined T3 and BAI treatment significantly increased Klotho levels, surpassing individual effects, and suppressed key signaling molecules (TGF, NFκB, GSK3), mitigating renal fibrosis and CKD complications, including cardiovascular disorders and dyslipidemia. This bidirectional approach, enhancing Klotho via T3 and sustained Wnt pathway inhibition, offers a novel and effective strategy for CKD management, particularly in elderly patients with hypothyroidism.
Longevity Relevance Analysis
(4)
The study claims that combined treatment with triiodothyronine and baicalein upregulates Klotho levels, mitigating chronic kidney disease and its complications in aged mice. This research is relevant as it addresses the interplay between aging, kidney function, and hormonal regulation, potentially targeting mechanisms that underlie age-related decline rather than merely treating symptoms.
Ghazal Darfarin, Janice Pluth
· Environmental and molecular mutagenesis
· Department of Health Physics and Diagnostic Sciences, University of Nevada, Las Vegas, Nevada, USA.
· pubmed
The mitochondria (mt) and nucleus engage in a dynamic bidirectional communication to maintain cellular homeostasis, regulating energy production, stress response, and cell fate. Anterograde signaling directs mt function, while retrograde signaling conveys metabolic and stress-rel...
The mitochondria (mt) and nucleus engage in a dynamic bidirectional communication to maintain cellular homeostasis, regulating energy production, stress response, and cell fate. Anterograde signaling directs mt function, while retrograde signaling conveys metabolic and stress-related changes from mt to the nucleus. Central to this crosstalk is mitochondrial DNA (mtDNA), which encodes key oxidative phosphorylation components. MtDNA integrity is preserved through quality control mechanisms, including fusion and fission dynamics, mitophagy, and nuclear-encoded DNA repair. Disruption in these pathways contributes to mt dysfunction, oxidative stress, and genetic instability-hallmarks of aging and diseases. Additionally, redox signaling and NAD+ homeostasis integrate mt and nuclear responses, modulating transcriptional programs that support mt biogenesis and stress adaptation. This review explores the molecular mechanisms coordinating mito-nuclear interactions, emphasizing their role in maintaining mtDNA integrity and cellular equilibrium. Understanding these processes provides insights into how mt dysfunction drives aging and disease, paving the way for targeted therapeutic strategies.
Longevity Relevance Analysis
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The paper discusses the mechanisms of mitochondrial-nuclear crosstalk and its role in maintaining mitochondrial DNA integrity, which is crucial for cellular health and longevity. This research is relevant as it addresses fundamental processes that contribute to aging and potential therapeutic strategies to mitigate age-related decline.
Lee, B., Ciciurkaite, G., Peng, S. ...
· epidemiology
· New York University
· medrxiv
Negative social ties, or "difficult ties," are pervasive yet understudied components of social networks that may accelerate biological aging and morbidity. Using ego-centric network data and DNA methylation-based biological aging clocks from a state representative probability sam...
Negative social ties, or "difficult ties," are pervasive yet understudied components of social networks that may accelerate biological aging and morbidity. Using ego-centric network data and DNA methylation-based biological aging clocks from a state representative probability sample in Indiana, we examine how negative social ties are associated with accelerated biological aging and a broad range of adverse physical and mental health outcomes. First, we find that difficult social ties are surprisingly common: on average, one in four network members is described as difficult, and nearly 60% of individuals report having at least one difficult tie. Regression analyses show that having more negative ties is associated with accelerated biological aging, with the most pronounced associations observed among individuals whose networks comprise more than 50% difficult ties. Finally, having negative ties is also associated with multiple adverse health outcomes beyond epigenetic aging, including poorer self-rated health, higher levels of depression and anxiety, elevated inflammation, greater multimorbidity, and unfavorable anthropometric indicators such as increased waist-to-hip ratio and BMI. These findings together highlight the critical role of negative social ties in biological aging as chronic stressors and the need for interventions that reduce the impact of negative social stressors within close social networks to promote healthier aging trajectories.
Longevity Relevance Analysis
(4)
Negative social ties are associated with accelerated biological aging and multiple adverse health outcomes. The paper explores the impact of social relationships on biological aging, which is a critical aspect of longevity research.
Toga, K., Oka, K., Tanaka, H. ...
· genomics
· Hiroshima University
· biorxiv
The naked mole rat (NMR, Heterocephalus glaber) is a eusocial rodent that is native to northeastern Africa. NMRs exhibit extraordinary traits such as longevity, resistance to age-related decline, and remarkable hypoxia tolerance. Although the reference genome of this species has ...
The naked mole rat (NMR, Heterocephalus glaber) is a eusocial rodent that is native to northeastern Africa. NMRs exhibit extraordinary traits such as longevity, resistance to age-related decline, and remarkable hypoxia tolerance. Although the reference genome of this species has been determined because of its unique characteristics, the significance or role of intraspecific genomic variations remains unknown. In this study, we used PacBio long-read sequencing to generate a genome assembly of NMR reared in Japan. The assembled genome is 2.56 Gb. Benchmarking Universal Single-Copy Orthologs (BUSCO) revealed high completeness (95.2%). BRAKER3 estimated 26,714 protein-coding genes, and we successfully added functional annotations for 26,232 protein-coding genes using the functional annotation workflow. We identified 417 gene models that were previously undetectable in the reference genome of this species. We also identified structural and amino acid sequence variations between our assembly and the reference genome, suggesting the presence of intraspecific genomic variations. This new genomic resource could help uncover the molecular mechanisms underlying the behavioral and physiological traits of NMR.
Longevity Relevance Analysis
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The paper presents a new genome assembly of the naked mole rat, which could help uncover molecular mechanisms underlying its extraordinary longevity and resistance to age-related decline. The study is relevant as it explores genomic variations that may contribute to the unique aging traits of the naked mole rat, a species known for its exceptional lifespan.
Daozheng Yang, Natalia Skinder, Yun-Ruei Kao ...
· Nature aging
· European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
· pubmed
During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration. This work uncovered that cell surface presentation of P-selectin (CD62P, encoded by Selp) increases in a large fraction of aging HSCs driv...
During aging, hematopoietic stem cell (HSC) function progressively declines which can lead to reduced blood cell production and regeneration. This work uncovered that cell surface presentation of P-selectin (CD62P, encoded by Selp) increases in a large fraction of aging HSCs driven by a proinflammatory milieu in mice. Notably, expression of P-selectin molecularly and functionally dichotomized the aging HSC pool; stem cells presenting with highly abundant P-selectin were hallmarked by aging-associated gene expression programs and reduced repopulation capacity upon regenerative stress. Ectopic expression of Selp in young HSCs was sufficient to impair long-term reconstitution potential and impair erythropoiesis. Mechanistically, we uncovered that P-selectin receptor activation by its primary ligand, P-selectin glycoprotein ligand-1, suppressed aging-associated gene expression, and, reversely, lack of P-selectin signaling led to HSC premature aging. Collectively, our study uncovered a functional role of P-selectin engagement in regulating HSC regeneration and driving stem cell aging when perturbed.
Longevity Relevance Analysis
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The paper claims that aberrant engagement of P-selectin contributes to hematopoietic stem cell aging and reduced regenerative capacity. This research is relevant as it addresses mechanisms underlying stem cell aging, which is a fundamental aspect of the aging process and could inform strategies for longevity and age-related regenerative decline.
Bianca Aparecida Martin, Juliana Viegas, Luciana Facco Dalmolin ...
· ACS biomaterials science & engineering
· School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Avenida do Café, s/n°, 14040-903 Ribeirão Preto, São Paulo, Brazil.
· pubmed
The skin is a complex organ composed of multiple layers and diverse cell types, including keratinocytes, fibroblasts, adipocytes, and sensory neurons, which maintain its structural and functional integrity together. Conventional in vitro and ex vivo models help investigate drug p...
The skin is a complex organ composed of multiple layers and diverse cell types, including keratinocytes, fibroblasts, adipocytes, and sensory neurons, which maintain its structural and functional integrity together. Conventional in vitro and ex vivo models help investigate drug permeation and selected biological effects. However, they are limited in replicating neural interactions critical for assessing the efficacy of neuropeptide-based therapies. To address this limitation, a sensory neuron-integrated skin spheroid (SS) model was established, incorporating key skin cell types and providing a rapid, adaptable, and physiologically relevant platform for screening the biological activity of topical delivery systems targeting neuronal pathways. The model's responsiveness was demonstrated using acetyl hexapeptide-3 (HEX-3), a neuropeptide that inhibits acetylcholine release. HEX-3 was internalized by spheroid cells, with preferential accumulation around sensory neurons, confirming targeted cellular uptake. In parallel, ex vivo human skin studies confirmed that HEX-3 can traverse the stratum corneum and accumulate in deeper layers. Treatment with this film enhanced skin hydration, reduced scaling, and improved the structural organization of the stratum corneum after 48 h. Functional assays using the SS model showed that HEX-3 treatment suppressed acetylcholine release, upregulated the antioxidant enzyme SOD2, and stimulated type I collagen synthesis. In aged skin samples, the application of HEX-3 significantly increased collagen levels. This effect was mirrored in the spheroid model, which reached collagen levels comparable to those of aged human skin upon treatment. These findings establish the SS model as a robust platform for evaluating the biological activity of neuropeptide-based topical therapies, offering valuable insights for developing advanced strategies for skin rejuvenation and repair.
Longevity Relevance Analysis
(4)
The paper claims that a sensory neuron-integrated skin spheroid model can effectively evaluate neuropeptide-based topical therapies for skin rejuvenation. This research is relevant as it addresses mechanisms related to skin aging and potential strategies for rejuvenation, which are important aspects of longevity research.
Yidong Zhu, Juan Zhao, Zihua Li ...
· Mammalian genome : official journal of the International Mammalian Genome Society
· Department of Traditional Chinese Medicine, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
· pubmed
Osteoporosis, characterized by decreased bone mineral density, is a common skeletal disorder in the aging population. Cellular senescence is a key factor in the pathophysiology of osteoporosis. This study aimed to identify senescence-related biomarkers and evaluate the functional...
Osteoporosis, characterized by decreased bone mineral density, is a common skeletal disorder in the aging population. Cellular senescence is a key factor in the pathophysiology of osteoporosis. This study aimed to identify senescence-related biomarkers and evaluate the functional role in osteoporosis by integrating microarray analysis, Mendelian randomization (MR), and experimental validation. Osteoporosis-related microarray dataset was downloaded from the Gene Expression Omnibus database for differential expression analysis. We integrated summary-level data from genome-wide association studies on osteoporosis with protein quantitative trait loci data to identify genes with causal relationships to osteoporosis. The senescence-related biomarker gene was identified using the SenMayo gene set and evaluated for the predictive performance through receiver operating characteristic (ROC) curve analysis. Functional enrichment analysis was conducted to explore the underlying mechanisms. Validation of gene expression was performed using quantitative real-time PCR in 50 clinical samples from patients with osteoporosis and controls. A total of 33 differentially expressed genes were identified between osteoporosis and control samples. MR analysis revealed 90 genes with causal effects on osteoporosis. Subsequently, CXCL1 was identified as the key senescence-related biomarker gene. ROC curve analysis demonstrated good predictive performance with an area under the curve value of 0.708. Functional enrichment analysis showed a significant association between CXCL1 and immune-related pathways in osteoporosis. The expression of the gene was successfully validated in clinical samples. This study identified and validated CXCL1 as a senescence-related biomarker with causal effects on osteoporosis through a combination of microarray analysis, MR, and experimental validation. These findings offer insights into the molecular mechanisms of osteoporosis and could inform the development of treatment strategies.
Longevity Relevance Analysis
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CXCL1 is identified as a senescence-related biomarker with causal effects on osteoporosis. The study addresses cellular senescence as a key factor in osteoporosis, linking it to aging and potentially informing treatment strategies that target the underlying mechanisms of age-related bone density loss.
Lorène Rousseau, Karina L Hajdu, Ping-Chih Ho
· Epigenesis, Genetic
· Department of Fundamental Oncology, University of Lausanne, 155 Ch. Des Boveresses, 1066, Epalinges, Switzerland.
· pubmed
Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. Th...
Epigenetic regulation, including DNA methylation and histone modifications, play a pivotal role in shaping T cell functionality throughout life. With aging, these epigenetic changes profoundly affect gene expression, altering T cell plasticity, activation, and differentiation. These modifications contribute significantly to immunosenescence, increasing susceptibility to infections, cancer, and autoimmune diseases. In CD8⁺ T cells, chromatin closure at key regulatory regions suppresses activation and migration, while chromatin opening in pro-inflammatory gene loci amplifies inflammation. These changes drive terminal differentiation, characterized by increased expression of senescence-associated markers, impaired migration and loss of epigenetic plasticity. CD4⁺ T cells experience fewer but critical epigenetic alterations, including disrupted pathways, a skewed Th1/Th2 balance, and reduced Treg functionality. These epigenetic changes, compounded by metabolic dysfunctions, such as mitochondrial deficiency and oxidative stress, impair T-cell adaptability and resilience in the aging organism. Therefore, understanding the interplay between epigenetic and metabolic factors in T cell aging offers promising therapeutic opportunities to mitigate immunosenescence and enhance immune function in aging populations. This review explores the interplay between DNA methylation, histone alterations, and metabolic changes underlying T cell aging.
Longevity Relevance Analysis
(4)
The paper claims that epigenetic and metabolic changes in T cells contribute to immunosenescence and age-related dysfunction. This research is relevant as it addresses the underlying mechanisms of aging at the cellular level, potentially offering insights into interventions that could enhance immune function in aging populations.
Dantong Zhu, Judy Z Wu, Patrick T Griffin ...
· npj aging
· Institute for Systems Biology, Seattle, WA, USA.
· pubmed
Frailty is an age-related geriatric syndrome. We performed a longitudinal study of aging female (n = 40) and male (n = 47) C57BL/6NIA mice, measured frailty index and derived metabolomics data from plasma. We identify age-related differentially abundant metabolites, determine fra...
Frailty is an age-related geriatric syndrome. We performed a longitudinal study of aging female (n = 40) and male (n = 47) C57BL/6NIA mice, measured frailty index and derived metabolomics data from plasma. We identify age-related differentially abundant metabolites, determine frailty-related metabolites, and generate frailty features, both in the whole cohort and sex-stratified subgroups. Using the features, we perform an association study and build a metabolomics-based frailty clock. We find that frailty-related metabolites are enriched for amino acid metabolism and metabolism of cofactors and vitamins, include ergothioneine, tryptophan and alpha-ketoglutarate, and present sex dimorphism. We identify B vitamin metabolism related flavin-adenine dinucleotide and pyridoxate as female-specific frailty biomarkers, and lipid metabolism related sphingomyelins, glycerophosphoethanolamine and glycerophosphocholine as male-specific frailty biomarkers. These associations are confirmed in a validation cohort, with ergothioneine and perfluorooctanesulfonate identified as robust frailty biomarkers. Our results identify sex-specific metabolite frailty biomarkers, and shed light on potential mechanisms.
Longevity Relevance Analysis
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The study identifies sex-specific metabolite biomarkers associated with frailty in aging mice. The research is relevant as it explores biological markers that could provide insights into the mechanisms of aging and frailty, potentially contributing to understanding the root causes of age-related decline.
Fiorenza Gianì, Benjamin B Roos, Patrick A Link ...
· American journal of physiology. Cell physiology
· Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
· pubmed
Idiopathic pulmonary fibrosis (IPF) is a fatal aging-related disease characterized by aberrant lung remodeling and progressive scarring, leading to organ failure and death. Current FDA approved anti-fibrotic treatments are unable to reverse established disease, highlighting the n...
Idiopathic pulmonary fibrosis (IPF) is a fatal aging-related disease characterized by aberrant lung remodeling and progressive scarring, leading to organ failure and death. Current FDA approved anti-fibrotic treatments are unable to reverse established disease, highlighting the need for innovative therapeutic approaches targeting novel pathways and cell types. Mounting evidence, including our own, has recently highlighted the pathogenic role of aging-related endothelial abnormalities, including vascular inflammation and oxidative stress, in the progression of lung fibrosis, offering new therapeutic opportunities to block IPF progression. Unexplored, however, are the modalities to restore vascular abnormalities associated with progressive lung fibrosis, representing a critical gap to effective treatments for IPF. In this study, we demonstrate that circulating extracellular vesicles (cEVs) isolated from young mice are capable of reversing the aging-associated transcriptional alterations of the pulmonary vasculature, reducing transcripts associated with innate immunity, oxidative stress and senescence, while simultaneously increasing transcripts linked to endothelial identity. Using the bleomycin model of persistent lung fibrosis in aged mice, we then demonstrate that the pre-treatment with cEVs improves the vascular response to injury and attenuates lung fibrosis progression, as demonstrated by reduced lung collagen content and preserved vascular network and lung architecture. These findings support the efficacy of interventions targeting endothelial aging-associated transcriptional alterations, such as young cEV delivery, in mitigating pulmonary fibrosis progression in animal models of persistent fibrosis and indicate the potential benefits of combined therapies that simultaneously address vascular and non-vascular aspects of IPF.
Longevity Relevance Analysis
(4)
The paper claims that circulating extracellular vesicles from young mice can reverse aging-associated transcriptional alterations in the pulmonary vasculature and mitigate lung fibrosis progression. This research addresses the underlying mechanisms of aging-related vascular dysfunction, which is crucial for developing therapies that target the root causes of age-related diseases.