Sharma, A., Mistry, M., Yao, P. ...
· cell biology
· Harvard T. H. Chan School of Public Health
· biorxiv
Aging results in a loss of metabolic flexibility during fasting, characterized by the inability to acutely switch between metabolic substrates and reduced lipid mobilization. However, the drivers of these effects intracellularly remain unclear. Here, in Caenorhabditis elegans, we...
Aging results in a loss of metabolic flexibility during fasting, characterized by the inability to acutely switch between metabolic substrates and reduced lipid mobilization. However, the drivers of these effects intracellularly remain unclear. Here, in Caenorhabditis elegans, we show that loss of coordinated inter-organelle dynamics causally initiates metabolic inflexibility with age. In young animals, peroxisomes emerge as the priming orchestrators of the fasting response, simultaneously governing lipid droplets (LDs) utilization and mitochondrial bioenergetics. With age, peroxisomal priming is lost, leading to mitochondrial fragmentation and impaired dynamic nutrient responses during fasting. Notably, dietary restriction (DR) exerts a rejuvenating effect on peroxisomal function, thereby preserving mitochondrial integrity and promoting longevity. Our study uncovers the expansive network of organelles enabling lipid mobilization during youth, providing critical context to the poorly understood role of peroxisomes in actively maintaining organelle homeodynamics and metabolic flexibility throughout the aging process.
Longevity Relevance Analysis
(5)
Loss of peroxisomal function leads to metabolic inflexibility during aging, which can be mitigated by dietary restriction. This study addresses the underlying mechanisms of aging and metabolic flexibility, contributing to the understanding of longevity and potential interventions.
Yu Yang Ng, Andy Tay
· Aging cell
· Department of Biomedical Engineering, National University of Singapore, Singapore City, Singapore.
· pubmed
Ageing is an inevitable biological process that impacts the immune system, leading to immunosenescence and inflammaging, which contribute to increased susceptibility to infections, autoimmune diseases and cancers in individuals over the age of 65. This review focuses on the agein...
Ageing is an inevitable biological process that impacts the immune system, leading to immunosenescence and inflammaging, which contribute to increased susceptibility to infections, autoimmune diseases and cancers in individuals over the age of 65. This review focuses on the ageing of lymph node stromal cells (LNSCs), which are crucial for maintaining lymph node (LN) structure and function. Age-related changes in LNs, such as fibrosis and lipomatosis, disrupt the LN architecture and reduce immune cell recruitment and function, impairing immune responses to infections and vaccinations. The review discusses the structural and functional decline of various LNSC subsets, including fibroblastic reticular cells (FRCs), lymphatic endothelial cells (LECs) and blood endothelial cells (BECs), highlighting their roles in immune cell activation and homeostasis. Potential strategies to restore aged LNSC function, such as enhancing LNSC activation during vaccination and using senotherapeutics, are explored. Outstanding questions regarding the mechanisms of LNSC ageing and how ageing of the LN stroma might impact autoimmune disorders are also addressed. This review aims to stimulate further research into the characterisation of aged LNSCs and the development of therapeutic interventions to improve immune function in the older adults.
Longevity Relevance Analysis
(4)
The paper discusses the structural and functional decline of lymph node stromal cells with age and explores potential strategies to restore their function. This research is relevant as it addresses the underlying mechanisms of immune system aging, which is a critical aspect of longevity and age-related diseases.
Xuming Zhu, Mingang Xu, Celine Portal ...
· Meibomian Glands
· Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
· pubmed
Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and...
Meibomian glands secrete lipid-rich meibum, which prevents tear evaporation. Aging-related Meibomian gland shrinkage may result in part from stem cell exhaustion and is associated with evaporative dry eye disease, a common condition lacking effective treatment. The identities and niche of Meibomian gland stem cells and the signals controlling their activity are poorly defined. Using snRNA-seq, in vivo lineage tracing, ex vivo live imaging, and genetic studies in mice, we identify markers for stem cell populations that maintain distinct regions of the gland and uncover Hedgehog (Hh) signaling as a key regulator of stem cell proliferation. Consistent with this, we show that human Meibomian gland carcinoma exhibits increased Hh signaling. Aged glands display decreased Hh and EGF signaling, deficient innervation, and loss of collagen I in niche fibroblasts, indicating that alterations in both glandular epithelial cells and their surrounding microenvironment contribute to age-related degeneration. These findings suggest new approaches to treat aging-associated Meibomian gland loss.
Longevity Relevance Analysis
(4)
The paper identifies Meibomian gland stem cell populations and their regulatory mechanisms, highlighting the role of Hedgehog signaling in aging-related degeneration. The research addresses the underlying mechanisms of aging in a specific tissue, which is relevant to understanding and potentially mitigating age-related decline.
Miny, S., Runel, G., Chlasta, J. ...
· cell biology
· CNRS - University Lyon1
· biorxiv
Skin homeostasis and self-renewal are partially maintained by interfollicular stem cells (ISCs), located in the basal layer above the dermal papillae of the dermo-epidermal junction (DEJ). Aging leads to a decline in skin renewal and a concurrent reduction in stem cell potential....
Skin homeostasis and self-renewal are partially maintained by interfollicular stem cells (ISCs), located in the basal layer above the dermal papillae of the dermo-epidermal junction (DEJ). Aging leads to a decline in skin renewal and a concurrent reduction in stem cell potential. It is also marked by disorganization of the extracellular matrix in both the DEJ and dermis, and flattening of the DEJ. To better understand ISC aging, new methods are needed to characterize ISCs and their environment. Since mechanical properties of cells and their substrate influence cell fate, we employed atomic force microscopy to explore whether ICSs niches and the DEJ exhibit distinct mechanical properties. Our findings reveal that ISCs possess greater stiffness than other basal cells, a mechanical signature that diminishes with age. Additionally, the DEJ beneath ISCs shows higher stiffness than under other basal cells, providing ISCs with a specific mechanical environment, which also deteriorates during aging. In vitro, sorting of ISCs based on MCSP expression effectively isolates ISCs beneath the dermal papillae, allowing the measurement of their mechanical signature and stemness potential under varying mechanical conditions. The study of ISC mechanical signatures offers a promising approach for characterizing 3D skin models and understanding defects in skin renewal and wound healing.
Longevity Relevance Analysis
(4)
Interfollicular stem cells exhibit a specific mechanical signature that diminishes with age, impacting skin renewal. The study addresses the aging process at the cellular level, focusing on the mechanical properties of stem cells, which is crucial for understanding and potentially mitigating age-related decline in skin health.
Laura Campello, Matthew J Brooks, Benjamin R Fadl ...
· Aging cell
· Neurobiology, Neurodegeneration and Repair Laboratory, National Eye Institute, National Institutes of Health, Bethesda, Maryland, USA.
· pubmed
Visual function deteriorates throughout the natural course of aging. Age-related structural and functional adaptations are observed in the retina, the light-sensitive neuronal tissue of the eye where visual perception begins. Molecular mechanisms underlying retinal aging are stil...
Visual function deteriorates throughout the natural course of aging. Age-related structural and functional adaptations are observed in the retina, the light-sensitive neuronal tissue of the eye where visual perception begins. Molecular mechanisms underlying retinal aging are still poorly understood, highlighting the need to identify biomarkers for better prognosis and alleviation of aging-associated vision impairment. Here, we investigate dynamics of transcriptional dysregulation in the retina and identify affected pathways within distinct retinal cell types. Using an optimized protocol for single-cell RNA sequencing of mouse retinas at 3, 12, 18, and 24 months, we detect a progressive increase in the number of differentially expressed genes across all retinal cell types. The extent and direction of expression changes varies, with photoreceptor, bipolar, and Müller cells showing the maximum number of differentially expressed genes at all age groups. Furthermore, our analyses uncover transcriptionally distinct, heterogeneous subpopulations of rod photoreceptors and bipolar cells, distributed across distinct areas of the retina. Our findings provide a plausible molecular explanation for enhanced susceptibility of rod cells to aging and correlate with the observed loss of scotopic sensitivity in elderly individuals.
Longevity Relevance Analysis
(4)
The paper identifies transcriptional dysregulation in the aging mouse retina, highlighting the molecular mechanisms underlying age-related visual impairment. This research is relevant as it explores the biological processes of aging in retinal cells, which could contribute to understanding and potentially mitigating age-related vision loss.
R Moaddel, J Candia, C Ubaida-Mohien ...
· Aging cell
· Biomedical Research Centre, National Institute on Aging, NIH, Baltimore, Maryland, USA.
· pubmed
The study of biomarkers in biofluids and tissues expanded our understanding of the biological processes that drive physiological and functional manifestations of aging. However, most of these studies were limited to examining one biological compartment, an approach that fails to ...
The study of biomarkers in biofluids and tissues expanded our understanding of the biological processes that drive physiological and functional manifestations of aging. However, most of these studies were limited to examining one biological compartment, an approach that fails to recognize that aging pervasively affects the whole body. The simultaneous modeling of hundreds of metabolites and proteins across multiple compartments may provide a more detailed picture of healthy aging and point to differences between chronological and biological aging. Herein, we report proteomic analyses of plasma and urine collected in healthy men and women, age 22-92 years. Using these data, we developed a series of metabolomic and proteomic predictors of chronological age for plasma, urine, and skeletal muscle. We then defined a biological aging score, which measures the departure between an individual's predicted age and the expected predicted age for that individual based on the full cohort. We show that these predictors are significantly and independently related to clinical phenotypes important for aging, such as inflammation, iron deficiency anemia, muscle mass, and renal and hepatic functions. Despite a different set of selected biomarkers in each compartment, the different scores reflect a similar degree of deviation from healthy aging in single individuals, thus allowing identification of subjects with significant accelerated or decelerated biological aging.
Longevity Relevance Analysis
(4)
The paper claims to develop metabolomic and proteomic predictors of biological aging across multiple physiological compartments. This research is relevant as it aims to understand the biological processes of aging and provides insights into biological aging versus chronological aging, which could inform strategies for healthy aging and longevity.
Das, P., Ravi, R., Singh, J.
· physiology
· Indian Institute of Science Education and Research Mohali, India
· biorxiv
Gut microbes play a crucial role in modulating host lifespan. However, the microbial factors that influence host longevity and their mechanisms of action remain poorly understood. Using the expression of Caenorhabditis elegans FAT-7, a stearoyl-CoA 9-desaturase, as a proxy for li...
Gut microbes play a crucial role in modulating host lifespan. However, the microbial factors that influence host longevity and their mechanisms of action remain poorly understood. Using the expression of Caenorhabditis elegans FAT-7, a stearoyl-CoA 9-desaturase, as a proxy for lifespan modulation, we conduct a genome-wide bacterial mutant screen and identify 26 Escherichia coli mutants that enhance host lifespan. Transcriptomic and biochemical analyses reveal that these mutant diets induce oxidative stress and activate the mitochondrial unfolded protein response (UPRmt). Lifespan extension requires the oxidative stress response regulators SKN-1, SEK-1, and HLH-30. Mechanistically, these effects are linked to reduced iron availability, as iron supplementation restores FAT-7 expression, suppresses UPRmt activation, and abolishes lifespan extension. Iron chelation mimics the pro-longevity effects of the mutant diets, highlighting dietary iron as a key modulator of aging. Our findings reveal a bacterial-host metabolic axis that links iron homeostasis, oxidative stress, and longevity in C. elegans.
Longevity Relevance Analysis
(4)
An iron-deplete diet enhances the lifespan of Caenorhabditis elegans by activating oxidative stress response pathways. The study addresses the modulation of lifespan through dietary factors and their underlying mechanisms, contributing to the understanding of aging processes.
Menzel, L., Zschummel, M., O'Melia, M. J. ...
· immunology
· Edwin L. Steele Laboratories, Massachusetts General Hospital, Harvard Medical School
· biorxiv
A diverse naive CD8 T cell repertoire is essential to provide broad protection against infection and cancer. Aging diminishes naive T cells, reducing potential diversity and leading to lymph node contraction. Here, we revealed that this decline occurs earlier in males, resulting ...
A diverse naive CD8 T cell repertoire is essential to provide broad protection against infection and cancer. Aging diminishes naive T cells, reducing potential diversity and leading to lymph node contraction. Here, we revealed that this decline occurs earlier in males, resulting in significant sex differences in immunity during middle age. Earlier in life, naive CD8 T cells in males become virtual memory cells prone to premature senescence. Due to androgen-driven thymic atrophy in males, naive CD8 T cells are insufficiently replenished. Therapeutic thymus rejuvenation via testosterone ablation restored naive CD8 T cells in lymph nodes of middle-aged male mice, leading to enhanced tumor recognition. These findings show the crucial role of sex and age on lymph node T cell repertoires and suggest potential strategies to restore immune function in males during aging.
Longevity Relevance Analysis
(4)
The paper claims that therapeutic thymus rejuvenation via testosterone ablation can restore naive CD8 T cells in middle-aged male mice, enhancing tumor recognition. This research addresses the underlying mechanisms of immune aging and suggests potential interventions to improve immune function, which is directly relevant to longevity and age-related health.
Xin Huang, Chenzhong Xu, Jie Zhang ...
· Myostatin
· Shenzhen Key Laboratory for Systemic Aging and Intervention (SKL-SAI), National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, School of Basic Medical Sciences, Shenzhen University Medical School, Shenzhen, China.
· pubmed
Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in ...
Exercise can improve health via skeletal muscle remodeling. Elucidating the underlying mechanism may lead to new therapeutics for aging-related loss of skeletal muscle mass. Here, we show that endurance exercise suppresses expression of YT521-B homology domain family (Ythdf1) in skeletal muscle, which recognizes the N6-methyladenosine (m6A). Ythdf1 deletion phenocopies endurance exercise-induced muscle hypertrophy in mice increases muscle mitochondria content and type I fiber specification. At the molecular level, Ythdf1 recognizes and promotes the translation of m6A-modified Mstn mRNA, which encodes a muscle growth inhibitor, Myostatin. Loss of Ythdf1 leads to hyperactivation of skeletal muscle stem cells (MuSCs), also called satellite cells (SCs), enhancing muscle growth and injury-induced regeneration. Our data reveal Ythdf1 as a key regulator of skeletal muscle homeostasis, provide insights into the mechanism by which endurance exercise promotes skeletal muscle remodeling and highlight potential strategies to prevent aging-related muscle degeneration.
Longevity Relevance Analysis
(5)
Endurance exercise suppresses Ythdf1 to enhance muscle growth and regeneration by inhibiting myostatin expression. This research addresses the mechanisms underlying muscle remodeling in the context of aging, which is directly related to combating age-related muscle degeneration.
Amanda E Coleman, Kate E Creevy, Rozalyn Anderson ...
· GeroScience
· Department of Small Animal Medicine and Surgery, University of Georgia, Athens, GA, USA. [email protected].
· pubmed
Companion dogs are a powerful model for aging research given their morphologic and genetic variability, risk for age-related disease, and habitation of the human environment. In addition, the shorter life expectancy of dogs compared to human beings provides a unique opportunity f...
Companion dogs are a powerful model for aging research given their morphologic and genetic variability, risk for age-related disease, and habitation of the human environment. In addition, the shorter life expectancy of dogs compared to human beings provides a unique opportunity for an accelerated timeline to test interventions that might extend healthy lifespan. The Test of Rapamycin In Aging Dogs (TRIAD) randomized clinical trial is a parallel-group, double-masked, randomized, placebo-controlled, multicenter trial that will test the ability of rapamycin to prolong lifespan and improve several healthspan metrics in healthy, middle-aged dogs recruited from Dog Aging Project participants. Here, we describe the rationale, design, and goals of the TRIAD randomized clinical trial, the first rigorous test of a pharmacologic intervention against biological aging with lifespan and healthspan metrics as endpoints to be performed outside of the laboratory in any species.
Longevity Relevance Analysis
(5)
The paper claims that rapamycin can prolong lifespan and improve healthspan metrics in healthy middle-aged dogs. The study is relevant as it aims to test a pharmacologic intervention against biological aging, potentially providing insights into lifespan extension and healthspan improvement in a model that closely interacts with human environments.
Angela M Tuckowski, Safa Beydoun, Elizabeth S Kitto ...
· eLife
· Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, United States.
· pubmed
Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that
Flavin-containing monooxygenases (FMOs) are a conserved family of xenobiotic enzymes upregulated in multiple longevity interventions, including nematode and mouse models. Previous work supports that
Longevity Relevance Analysis
(4)
The paper suggests that flavin-containing monooxygenases (FMOs) play a role in longevity interventions across different model organisms. The focus on FMOs and their upregulation in longevity interventions indicates a potential link to mechanisms of aging and lifespan extension.
Tianyuan Gu, Yong He, Jianan Zhou ...
· Nucleus Pulposus
· Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
· pubmed
Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, with limited effective treatments due to an incomplete understanding of disease mechanisms. In this study, we report that circFUNDC1, a nuclear circular RNA, is markedly downregulated in nucleus pulposus...
Intervertebral disc degeneration (IVDD) is a leading cause of low back pain, with limited effective treatments due to an incomplete understanding of disease mechanisms. In this study, we report that circFUNDC1, a nuclear circular RNA, is markedly downregulated in nucleus pulposus cells (NPCs) from patients with end-stage IVDD. CircFUNDC1 is derived from the gene encoding the FUN14 domain-containing 1 (FUNDC1) protein, which is essential for mitophagy and cell survival. Functional analyses reveal that circFUNDC1 plays a crucial role in maintaining extracellular matrix homeostasis by enhancing the expression of anabolic factors in NPCs. Additionally, we identified the transcriptional regulator cyclin-dependent kinase 9 (CDK9) as a novel binding partner for circFUNDC1. Binding with circFUNDC1 recruits CDK9 via complementary nucleotides to the FUNDC1 promoter to stimulate the production of full-length FUNDC1 mRNAs and proteins, forming a positive feedback loop. Overexpression of circFUNDC1 protects NPCs from oxidative stress by promoting mitophagy, reducing reactive oxygen species levels, and inhibiting cellular senescence. Moreover, circFUNDC1 overexpression delays the onset of IVDD in an ex-vivo culture model. This study is the first to demonstrate that circFUNDC1 is vital for protecting NPCs from oxidative stress, suggesting circFUNDC1 as a potential therapeutic target for IVDD.
Longevity Relevance Analysis
(4)
CircFUNDC1 overexpression protects nucleus pulposus cells from oxidative stress and delays intervertebral disc degeneration. The study addresses a mechanism related to cellular senescence and oxidative stress, which are key factors in aging and age-related degeneration.
Qiuting Wen, Joseph Muskat, Charles F Babbs ...
· Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
· Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
· pubmed
Intracranial cardiac impulse propagation along penetrating arterioles is vital for both nutrient supply via blood circulation and waste clearance via CSF circulation. However, current neuroimaging methods are limited to simultaneously detecting impulse propagation at pial arterie...
Intracranial cardiac impulse propagation along penetrating arterioles is vital for both nutrient supply via blood circulation and waste clearance via CSF circulation. However, current neuroimaging methods are limited to simultaneously detecting impulse propagation at pial arteries, arterioles, and between them. We hypothesized that this propagation could be detected via paravascular CSF dynamics and that it may change with aging. Using dynamic diffusion-weighted imaging (dynDWI), we detected oscillatory CSF motion synchronized with the finger photoplethysmography in the subarachnoid space (SAS) and cerebral cortex, with a delay revealing an impulse propagation pathway from the SAS to the cortex, averaging 84 milliseconds. Data from 70 subjects aged 18 to 85 years showed a bimodal age-related change in the SAS-Cortex travel time: it initially increases with age, peaks around 45 years, then decreases. Computational biomechanical modeling of the cardiovascular system was performed and replicated this 84-millisecond delay. Sensitivity analysis suggests that age-related variations in travel time are primarily driven by changes in arteriolar compliance. These findings support the use of dynDWI for measuring intracranial impulse propagation and highlight its potential in assessing related vascular and waste clearance functions.
Longevity Relevance Analysis
(4)
The paper claims that aging affects the travel time of intracranial cardiac impulse propagation, which can be measured using dynamic diffusion-weighted imaging. This research is relevant as it explores the physiological changes associated with aging that could impact vascular health and waste clearance, potentially addressing underlying mechanisms of age-related decline.
Severin Haider, Eliza Sassu, Dragana Stefanovska ...
· Enteric Nervous System
· Institute of Experimental and Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Freiburg, Freiburg 79110, Germany.
· pubmed
Aging strongly affects the peripheral nervous system (PNS), triggering alterations that vary depending on the innervated tissue. The most frequent alteration in peripheral nerve aging is reduced nerve fiber and glial density which can lead to abnormal nerve functionality. Interes...
Aging strongly affects the peripheral nervous system (PNS), triggering alterations that vary depending on the innervated tissue. The most frequent alteration in peripheral nerve aging is reduced nerve fiber and glial density which can lead to abnormal nerve functionality. Interestingly, the activation of a destructive phenotype takes place in macrophages across the PNS while a reduced number of neuronal bodies is a unique feature of some enteric ganglia. Single cell/nucleus RNA-sequencing has unveiled a striking complexity of cell populations in the peripheral nerves, and these refined cell type annotations could facilitate a better understanding of PNS aging. While the effects of senescence on individual PNS cell types requires further characterization, the use of senolytics appears to improve general PNS function in models of aging. Here, we review the current understanding of age-related changes of the intracardiac, musculoskeletal, and enteric nervous system sub-sections of the PNS, highlighting their commonalities and differences.
Longevity Relevance Analysis
(4)
The paper reviews age-related changes in the peripheral nervous system and discusses potential interventions like senolytics. The focus on understanding and potentially mitigating the effects of aging on the PNS aligns with longevity research goals.
Danitra Parker, Kanisa Davidson, Pawel A Osmulski ...
· Aging cell
· Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
· pubmed
The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a ma...
The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains, including in the hippocampus, this is driven by reduced functionality of aged proteasome. The decline in proteasome activity is matched by a decline in 20S proteasome assembly. In contrast, 26S proteasome assembly was found to increase with age, though 26S proteasome activity was still found to decline. Our data suggests that age-related declines in proteasome activity is driven predominantly by reduced functionality of proteasome rather than altered composition. By overexpressing the proteasome subunit PSMB5 in the neurons of mice to increase the proteasome content and thus enhance its functionality, we slowed age-related declines in spatial learning and memory. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.
Longevity Relevance Analysis
(5)
The paper claims that augmenting proteasome function can mitigate age-related cognitive decline in mice. This research addresses a potential root cause of cognitive decline associated with aging, suggesting a therapeutic strategy that could have implications for longevity and age-related cognitive diseases.
Ying Zou, Mibu Cao, Meiling Tai ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China.
· pubmed
The decrease in fibroblast collagen is a primary contributor to skin aging. Lactate can participate in collagen synthesis through lysine lactylation by regulating gene transcription. However, the precise mechanism by which lactate influences collagen synthesis requires further in...
The decrease in fibroblast collagen is a primary contributor to skin aging. Lactate can participate in collagen synthesis through lysine lactylation by regulating gene transcription. However, the precise mechanism by which lactate influences collagen synthesis requires further investigation. This study demonstrates that the depletion of macrophages mitigates the stimulating effect of lactate on collagen synthesis in fibroblasts. Through joint CUT&Tag and RNA-sequencing analyses, a feedback loop between H4K12 lactylation (H4K12la) and histone deacetylase 3 (HDAC3) in macrophages that drives lactate-induced collagen synthesis are identified. Macrophages can uptake extracellular lactate via monocarboxylate transporter-1 (MCT1), leading to an up-regulation of H4K12la levels through a KAT5-KAT8-dependent mechanism in response to Poly-L-Lactic Acid (PLLA) stimulation, a source of low concentration and persistent lactate, thereby promoting collagen synthesis in fibroblasts. Furthermore, H4K12la is enriched at the promoters of TGF-β1 and TGF-β3, enhancing their transcription. Hyperlactylation of H4K12la inhibits the expression of the eraser HDAC3, while the activation of HDAC3 reduces H4K12la in macrophages and suppresses collagen synthesis in fibroblasts. In conclusion, this study illustrates that macrophages play a critical role in lactate-induced collagen synthesis in the skin, and targeting the lactate-H4K12la-HDAC3-TGF-β axis may represent a novel approach for enhancing collagen production to combat skin aging.
Longevity Relevance Analysis
(4)
The study claims that macrophages regulate lactate-induced collagen synthesis in fibroblasts through a feedback loop involving H4K12 lactylation and HDAC3. This research is relevant as it addresses mechanisms that could potentially enhance collagen production, which is directly linked to skin aging and may contribute to strategies for combating age-related skin deterioration.
Lei Qi, Jing Wang, Jinge Yan ...
· Journal of nanobiotechnology
· Department of Oral & Cranio-Maxillofacial Surgery, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai Jiao Tong University School of Medicine, National Clinical Research Center for Oral Diseases, Shanghai, 200011, PR China.
· pubmed
Senescent mandibular bone repair poses a formidable challenge without a completely satisfactory strategy. Endogenous cell recruitment and osteogenic differentiation are two sequential stages in bone regeneration, and disruptions in these two processes present significant obstacle...
Senescent mandibular bone repair poses a formidable challenge without a completely satisfactory strategy. Endogenous cell recruitment and osteogenic differentiation are two sequential stages in bone regeneration, and disruptions in these two processes present significant obstacles to senescent bone repair. To address these issues, engineered extracellular vesicles (EV) with sequential stem cell recruitment and osteogenic functions were developed. This study demonstrated that Apt19s-engineered extracellular vesicles (Apt19s-EV) recognize and recruit bone marrow mesenchymal stem cells derived from old rats (O-BMSCs) specifically and effectively. MiR-376b-5p, identified by RNA sequencing and transfection, was significantly decreased in O-BMSCs, and it was selected to construct miR-376b-5p-engineered extracellular vesicles (376b-EV). 376b-EV could promote osteogenesis and alleviate senescence of O-BMSCs by targeting Camsap1. To combine the advantages of Apt19s and miR-376b-5p, dual engineered extracellular vesicles (Apt-376b-EV) comprising both Apt19s and miR-376b-5p modifications were constructed. To further validate its function, Gelatin methacryloyl (GelMA) hydrogel was used as a carrier to construct the Apt-376b-EV@GelMA delivery system. The in vitro results have demonstrated that Apt-376b-EV@GelMA could recruit O-BMSCs, alleviate senescence and promote osteogenic differentiation sequentially. Notably, the in vivo study also showed that Apt-376b-EV@GelMA could sequentially recruit endogenous stem cells and enhance new bone formation in senescent bone fracture and critical-sized defect models. In summary, the dual engineered extracellular vesicles, Apt-376b-EV, offer an appealing solution for recruiting endogenous stem cells and promoting bone repair sequentially in the senescent microenvironment, which may broaden the clinical applications of engineered EV and provide valuable strategies for treating senescent bone-related diseases in the future clinical work.
Longevity Relevance Analysis
(4)
The paper claims that dual engineered extracellular vesicles can sequentially recruit stem cells and promote osteogenic differentiation to enhance bone repair in a senescent microenvironment. This research is relevant as it addresses mechanisms of bone regeneration in the context of aging, potentially offering insights into therapies that target the underlying processes of age-related bone degeneration.
Cui Guan, Abigail Otchere, Mihails Laskovs ...
· Aging cell
· College of Health and Life Sciences, Aston University, Birmingham, UK.
· pubmed
Invertebrate models have been instrumental in advancing our understanding of the molecular mechanisms of ageing. The isolation of single gene mutations that both extend lifespan and improve age-related health have identified potential targets for therapeutic intervention to allev...
Invertebrate models have been instrumental in advancing our understanding of the molecular mechanisms of ageing. The isolation of single gene mutations that both extend lifespan and improve age-related health have identified potential targets for therapeutic intervention to alleviate age-related morbidity. Here, we find that genetic loss of function of the G protein-coupled metabotropic glutamate receptor (DmGluRA) in Drosophila extends the lifespan of female flies. This longevity phenotype was accompanied by lower basal levels of oxidative stress and improved stress tolerance, and differences in early-life behavioural markers. Gene expression changes in DmGluRA mutants identified reduced ribosome biogenesis, a hallmark of longevity, as a key process altered in these animals. We further show that the pro-longevity effects of reduced DmGluRA signalling are dependent on the fly homologue of Fragile X Mental Retardation Protein (FMRP), an important regulator of ribosomal protein translation. Importantly, we can recapitulate lifespan extension using a specific pharmacological inhibitor of mGluR activity. Hence, our study identifies metabotropic glutamate receptors as potential targets for age-related therapeutics.
Longevity Relevance Analysis
(4)
The paper claims that genetic and pharmacological inhibition of metabotropic glutamate receptor signalling extends lifespan in Drosophila. This research identifies a potential target for therapeutic intervention in the aging process, focusing on mechanisms that could alleviate age-related morbidity rather than merely addressing symptoms.
Vera Middelkamp, Eliisa Kekäläinen
· GeroScience
· Translational Immunology Research Program and Dept. of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland.
· pubmed
Age-associated thymic involution leads to a significant decline in thymic T cell output, a major contributor to immunosenescence in the elderly. Accurately measuring thymic output is therefore critical for understanding the mechanisms behind immune aging. Furthermore, robust quan...
Age-associated thymic involution leads to a significant decline in thymic T cell output, a major contributor to immunosenescence in the elderly. Accurately measuring thymic output is therefore critical for understanding the mechanisms behind immune aging. Furthermore, robust quantification of thymic output is essential in various other clinical and research settings, including the diagnosis of immunodeficiencies and the monitoring of T cell reconstitution following therapeutic interventions like hematopoietic stem cell transplantation. Current methodologies for measuring thymic output include T cell receptor excision circle (TREC) quantification via quantitative polymerase chain reaction and the enumeration of recent thymic emigrants (RTEs) using flow cytometry. However, TREC-based assays are inherently insensitive to subtle changes in thymic output, limiting their applicability beyond neonatal immunodeficiency screening. Similarly, RTE enumeration presents challenges; while surface markers exist for CD4⁺ RTEs, validated markers for CD8⁺ cytotoxic T lymphocytes are lacking. This represents a significant knowledge gap, particularly as aging has been shown to disproportionally affect the CD8 T cell pool. Moreover, while flow cytometry effectively measures mature naïve T cells, these cells do not accurately represent real-time thymic output, as they can persist in peripheral circulation for extended periods. These limitations highlight the pressing need for more accurate and sensitive methods to assess thymic output. Improved measurement techniques would not only enhance our understanding of thymic involution in the context of aging but also enable large-scale investigations into thymic function and the mechanisms driving its decline in both health and disease. In this review, we examine current methodologies for measuring thymic output in humans, critically evaluate their limitations, and discuss emerging approaches to address these gaps in the field.
Longevity Relevance Analysis
(4)
The paper discusses the need for improved methodologies to measure thymic output, which is crucial for understanding immune aging and its implications for longevity. The focus on thymic involution and its impact on immune function directly addresses mechanisms of aging, making it relevant to longevity research.
Yehui Gao, Xinyun Zhang, Congmin Wei ...
· Aging cell
· School of Life Sciences and Technology, Shanghai East Hospital, Institute for Regenerative Medicine, Tongji University, Shanghai, China.
· pubmed
As global life expectancy increases, the focus has shifted from merely extending lifespan to promoting healthy aging. GSTA1, GSTA2, and GSTA3 (GSTA1-3), members of the alpha class of glutathione S-transferases, are involved in diverse biological processes, including metabolism an...
As global life expectancy increases, the focus has shifted from merely extending lifespan to promoting healthy aging. GSTA1, GSTA2, and GSTA3 (GSTA1-3), members of the alpha class of glutathione S-transferases, are involved in diverse biological processes, including metabolism and immune regulation, highlighting their potential influence on human health span and lifespan. In this study, we employed Caenorhabditis elegans as a model organism to investigate the role of gst-35, an ortholog of mammalian GSTA1-3, in healthy aging. Our results demonstrated that gst-35 overexpression has detrimental effects on multiple physiological functions in nematodes. Specifically, gst-35 overexpression significantly reduced lifespan, impaired development and growth, and substantially diminished reproductive capacity, physical fitness, and stress resistance. In contrast, gst-35 knockout partially enhanced physical fitness and stress resistance. Comprehensive RNA-sequencing transcriptome analysis revealed that gst-35 overexpression disrupted metabolic homeostasis and induced lysosomal dysfunction. These effects were mediated through the activation of the pmk-1 signaling pathway and suppression of skr genes, which collectively impaired healthy aging processes. These findings illuminate the complex role of gst-35 in aging and provide valuable insights into the molecular mechanisms underlying healthy aging, offering potential targets for interventions aimed at promoting health span.
Longevity Relevance Analysis
(4)
The paper claims that overexpression of gst-35 negatively impacts health span in C. elegans through lysosomal dysfunction. This research is relevant as it investigates the molecular mechanisms underlying healthy aging, focusing on the role of specific genes in promoting or impairing health span, which aligns with the goals of longevity research.
Sivakumar, S., LeFebre, R., Menichetti, G. ...
· bioengineering
· University of Pittsburgh
· biorxiv
Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middl...
Maintenance of organismal function requires tightly regulated biomolecular communication. However, with aging, communication deteriorates, thereby disrupting effective information flow. Using information theory applied to skeletal muscle single cell RNA-seq data from young, middle-aged, and aged animals, we quantified the loss of communication efficiency over time. We considered communication channels between transcription factors (TF; input message) and corresponding target genes (TG; output message). Mutual information (MI), defined as the information effectively transmitted between TFs and TGs, declined with age. This decline was attributed to escalating biological noise and loss of precision with which TFs regulate TGs (i.e., channel capacity). When we ranked TF:TG pairs by MI, pairs associated with fatty acid oxidation displayed the greatest loss of communication with aging, while the system preserved communication between pairs related to RNA synthesis. These data suggest ineffective communication with aging against a backdrop of resource reallocation to support essential cellular functions.
Longevity Relevance Analysis
(4)
The paper claims that the fidelity of genetic information transfer declines with aging in skeletal muscle due to increased biological noise and loss of precision in transcription factor regulation. This research is relevant as it addresses the mechanisms underlying aging at a molecular level, potentially contributing to our understanding of the root causes of aging and age-related dysfunctions.
Robinson, T. D., Sun, Y. L., Chang, P. T. H. ...
· neuroscience
· Rotman Research Institute, Baycrest
· biorxiv
One of the most promising interventional targets for brain health is cerebral perfusion, but its link to white matter (WM) aging remains unclear. Motivated by existing literature demonstrating links between declining cortical perfusion and the development of WM hyperintensities, ...
One of the most promising interventional targets for brain health is cerebral perfusion, but its link to white matter (WM) aging remains unclear. Motivated by existing literature demonstrating links between declining cortical perfusion and the development of WM hyperintensities, we posit that regional WM hypoperfusion precedes deteriorating WM integrity. Using the Human Connectome Project Aging (HCP-A) data set, we examine tract-wise associations between WM microstructural integrity (i.e. fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) and perfusion (i.e. cerebral blood flow and arterial transit time) in ten major bilateral WM tracts. Results show that tracts displaying the largest CBF decline in aging do not necessarily display the largest ATT decline, and vice versa. Moreover, significant WM perfusion-microstructure canonical correlations were found in all tracts, but the drivers of these correlations vary by both tract and sex, with female subjects demonstrating more tracts with large microstructural variations contributing to the correlations. Additionally, arterial transit time appears to be the earliest indicator of WM declines, preceding age-related microstructural differences and CBF in several tracts. This study contributes compelling evidence to the vascular hypothesis of WM degeneration, and highlights the utility of blood-flow timing as an early marker of aging.
Longevity Relevance Analysis
(4)
Regional white matter hypoperfusion precedes deteriorating white matter integrity in aging. This study is relevant as it explores the vascular mechanisms underlying white matter degeneration, which could inform interventions aimed at promoting brain health and longevity.
Zhi-Peng Li, Zhaozhen Du, De-Shuang Huang ...
· Deep Learning
· Ningbo Institute of Digital Twin, Eastern Institute of Technology, Ningbo, 315201, Zhejiang, China.
· pubmed
Deep learning (DL) and explainable artificial intelligence (XAI) have emerged as powerful machine-learning tools to identify complex predictive data patterns in a spatial or temporal domain. Here, we consider the application of DL and XAI to large omic datasets, in order to study...
Deep learning (DL) and explainable artificial intelligence (XAI) have emerged as powerful machine-learning tools to identify complex predictive data patterns in a spatial or temporal domain. Here, we consider the application of DL and XAI to large omic datasets, in order to study biological aging at the molecular level. We develop an advanced multi-view graph-level representation learning (MGRL) framework that integrates prior biological network information, to build molecular aging clocks at cell-type resolution, which we subsequently interpret using XAI. We apply this framework to one of the largest single-cell transcriptomic datasets encompassing over a million immune cells from 981 donors, revealing a ribosomal gene subnetwork, whose expression correlates with age independently of cell-type. Application of the same DL-XAI framework to DNA methylation data of sorted monocytes reveals an epigenetically deregulated inflammatory response pathway whose activity increases with age. We show that the ribosomal module and inflammatory pathways would not have been discovered had we used more standard machine-learning methods. In summary, the computational deep learning framework presented here illustrates how deep learning when combined with explainable AI tools, can reveal novel biological insights into the complex process of aging.
Longevity Relevance Analysis
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The paper presents a novel deep learning framework that uncovers molecular insights into aging through the analysis of single-cell and epigenetic data. This research is relevant as it addresses the underlying biological mechanisms of aging rather than merely focusing on age-related diseases or symptoms.
Man Zhu, Meng Ma, Lunan Luo ...
· Aging cell
· Department of Health Management & Institute of Health Management, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.
· pubmed
DNA topoisomerases are essential molecular machines that manage DNA topology in the cell and play important roles in DNA replication and transcription. We found that knocking down the enzyme topoisomerase Top2 or its mammalian homolog TOP2B increases the lifespan of S. cerevisiae...
DNA topoisomerases are essential molecular machines that manage DNA topology in the cell and play important roles in DNA replication and transcription. We found that knocking down the enzyme topoisomerase Top2 or its mammalian homolog TOP2B increases the lifespan of S. cerevisiae, C. elegans, and mice. TOP2B reduction also extends the health span of mice and alleviates the pathologies of aging in multiple tissues. At the cellular/molecular level, TOP2B reduction alleviates the major hallmarks of aging, including senescence, DNA damage, and deregulated nutrient sensing. We observed that TOP2B reduction changes the epigenetic landscape of various tissues in old mice toward that of the young animals, and differentially downregulates genes with active promoter and high expression. Our observations suggest that Top2 reduction confers pro-longevity effect across species possibly through a conserved mechanism and may be a promising strategy for longevity intervention.
Longevity Relevance Analysis
(5)
Reduction of DNA Topoisomerase Top2 extends lifespan and health span across species by reprogramming the epigenetic landscape. The study addresses mechanisms that could potentially mitigate the root causes of aging, making it relevant to longevity research.
Jian Zhang, Shunze Jia, Zehua Zheng ...
· GeroScience
· First Affiliated Hospital, Zhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang University, Hangzhou, Zhejiang, China.
· pubmed
The ovary is one of the first organs in humans to exhibit age-related functional impairments. As an organ composed of diverse heterogeneous cell types, the ovary exhibits cell-type-specific changes during the aging process, ultimately leading to a decline in female fertility. Inv...
The ovary is one of the first organs in humans to exhibit age-related functional impairments. As an organ composed of diverse heterogeneous cell types, the ovary exhibits cell-type-specific changes during the aging process, ultimately leading to a decline in female fertility. Investigating the molecular mechanisms of ovarian aging is crucial for understanding age-related fertility dysfunction in females. In this study, we combine scRNA-seq and scATAC-seq from mouse young/aged ovaries to characterize molecular features during ovarian aging. Using the single-cell multi-omic data, we revealed the cell-type-specific transcriptional changes during the aging process in seven major ovarian cell types and identified the cis/trans-regulatory elements governing these transcriptional changes. Specifically, we uncovered the transcriptional alterations of TGF-beta signaling in mesenchymal cells and endoplasmic reticulum stress in granulosa cells of aged mouse ovaries and further identified the potential corresponding cis/trans-regulatory elements. These molecular alterations may contribute to aging-induced functional impairments in mouse ovaries. In summary, this work provides transcriptome and chromatin accessibility landscape of ovarian aging in mice, which serve as a resource for identifying the cell-type-specific molecular mechanisms underlying ovarian aging, aiding in the identification of potential diagnostic biomarkers and treatment strategies.
Longevity Relevance Analysis
(4)
The study identifies cell-type-specific transcriptional changes and regulatory elements associated with ovarian aging in mice. This research is relevant as it investigates the molecular mechanisms underlying aging in the ovary, which is crucial for understanding age-related fertility dysfunction in females, thereby addressing a root cause of aging-related decline in reproductive health.
Felipe Cabral-Miranda, Ana Paula Bergamo Araujo, Danilo Bilches Medinas ...
· Aging cell
· Institute of Biomedical Sciences, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
· pubmed
Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the ...
Dementia, characterized by loss of cognitive abilities in the elderly, poses a significant global health challenge. This study explores the role of astrocytes, one of most representative glial cells in the brain, in mitigating cognitive decline. Specifically, we investigated the impact of Hevin (also known as SPARC-like1/SPARCL-1), a secreted glycoprotein, on cognitive decline in both normal and pathological brain aging. By using adeno-associated viruses, we overexpressed Hevin in hippocampal astrocytes of middle-aged APP/PSEN mice, an established Alzheimer's disease (AD) model. Results demonstrated that Hevin overexpression attenuates cognitive decline, as evidenced by cognitive tests, increased pre- and postsynaptic markers colocalization, and altered expression of synaptic mediators, as revealed by proteomic profiling. Importantly, Hevin overexpression did not influence the deposition of Aβ plaques in the hippocampus, a hallmark of AD pathology. Furthermore, the study extended its findings to middle-aged wild-type animals, revealing improved cognitive performance following astrocytic Hevin overexpression. In conclusion, our results propose astrocytic Hevin as a potential therapeutic target for age-associated cognitive decline.
Longevity Relevance Analysis
(4)
Astrocytic Hevin overexpression mitigates cognitive decline in both normal and pathological brain aging. The study addresses a potential therapeutic target that could influence mechanisms underlying cognitive decline associated with aging, rather than merely treating symptoms of age-related diseases.
Xin Fu, Yu Zhao, Xiwei Cui ...
· Chemokine CXCL9
· Research Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144, P. R. China.
· pubmed
Microvascular aging, predominantly driven by endothelial cells (ECs) dysfunction, is a critical early event in cardiovascular diseases. However, the specific effects of aging on ECs across the microvascular network segments and the associated mechanisms are not fully understood. ...
Microvascular aging, predominantly driven by endothelial cells (ECs) dysfunction, is a critical early event in cardiovascular diseases. However, the specific effects of aging on ECs across the microvascular network segments and the associated mechanisms are not fully understood. In this study, we detected a microvascular rarefaction and a decreased proportion of venular ECs in the subcutaneous adipose tissue of aged mice using light-sheet immunofluorescence microscopy and single-cell RNA sequencing. Moreover, aged ECs, especially in the venular subtype, exhibited a pseudotemporal transition to a terminal state characterized by diminished oxidative phosphorylation and strengthened cytokine signaling. Metabolic flux balance analysis predicted that among the 13 differentially expressed cytokines identified in aged EC subpopulations, Cxcl9 was strongly correlated with impaired oxidative phosphorylation in aged ECs. It was further validated using microvascular ECs treated with Cxcl9. Notably, the G protein-coupled receptor signaling pathway was subsequently suppressed, in which Aplnr suppression was also observed in aged ECs, contributing to their impaired energy metabolism and reduced angiogenesis. Based on these findings, we propose Cxcl9 as a biomarker for aging-related dysfunction of microvascular ECs, suggesting that targeting Cxcl9 signaling may help combat microvascular aging.
Longevity Relevance Analysis
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Cxcl9 is proposed as a biomarker for aging-related dysfunction of microvascular endothelial cells, suggesting that targeting Cxcl9 signaling may help combat microvascular aging. The study addresses mechanisms underlying endothelial cell dysfunction in aging, which is a root cause of age-related diseases, thus contributing to the understanding of aging processes.
Xiao Li, Yao Xu, Ting Li ...
· Aging
· Department of Pathology, Wuhan No. 1 Hospital, Wuhan 430022 China.
· pubmed
Cognitive impairment is a typical hallmark of aging in mice and humans. Here, we reported that downregulation of STAT1 improved learning and memory impairments in aging mice by enhancing the expression of synaptic protein and inhibiting the expression of inflammatory factors. Pro...
Cognitive impairment is a typical hallmark of aging in mice and humans. Here, we reported that downregulation of STAT1 improved learning and memory impairments in aging mice by enhancing the expression of synaptic protein and inhibiting the expression of inflammatory factors. Proteomic analysis revealed 139 differentially expressed proteins (DEPs) in the hippocampus of downregulated-STAT1 aging mice, compared with aging control mice. Functional classification of DEPs indicated that these mainly involved in inflammation, autophagy, synapse, mitochondria and apoptosis. The ClueGo analysis uncovered that the Wiki pathway of these DEPs were involved in proteasome degradation, IL-6 signaling pathway, signaling of hepatocyte growth factor receptor and so on. Taken together, downregulation of STAT1 may delay aging with multiple mechanisms.
Longevity Relevance Analysis
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Downregulation of STAT1 improves learning and memory impairments in aging mice. This study addresses a potential mechanism underlying cognitive decline in aging, which is a significant aspect of the aging process and could contribute to understanding interventions that target the root causes of age-related cognitive impairments.
M Borri, M E Jacobs, P Carmeliet ...
· American journal of physiology. Renal physiology
· Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, VIB Center for Cancer Biology, VIB, Leuven, 3000, Belgium.
· pubmed
Global population aging is an escalating challenge in modern society, especially as it impairs the function of multiple organs and increases the burden of age-related diseases. The kidneys, in particular, experience function decline, reduced regenerative capacity and increased su...
Global population aging is an escalating challenge in modern society, especially as it impairs the function of multiple organs and increases the burden of age-related diseases. The kidneys, in particular, experience function decline, reduced regenerative capacity and increased susceptibility to injury as they age. As a result, the prevalence of chronic kidney disease (CKD) rises with aging, further contributing to the growing health burden in older populations. One of the key factors in this process is the dysfunction of specialized renal endothelial cells (RECs), which are essential for maintaining kidney health by regulating blood flow, and supporting filtration, solute and water reabsorption, and vascular integrity. As the kidneys age, REC dysfunction drives vascular and microenvironmental changes, contributing to the overall decline in kidney function. In this review, we outline the structural and functional effects of aging on kidney's macrovascular and microvascular compartments and provide a phenotypic description of the aged endothelium. We particularly focus on the molecular and metabolic rewiring driving and sustaining growth-arrested EC senescence phenotype. We finally give an overview of senotherapies acting on ECs especially on those modulating metabolism. Given that the pathophysiological processes underlying kidney aging largely overlap with those observed in CKD, REC rejuvenation could also benefit CKD patients. Moreover, such interventions may hold promise in improving the outcomes of aged kidney transplants. Hence, advancing our understanding of REC and kidney aging will create opportunities for innovations that could improve outcomes for both elderly individuals and CKD patients.
Longevity Relevance Analysis
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The paper claims that rejuvenating renal endothelial cells could improve kidney function in aging and chronic kidney disease patients. This research is relevant as it addresses the underlying mechanisms of aging in kidney function, focusing on endothelial dysfunction, which is a critical aspect of age-related decline rather than merely treating symptoms.
Yuting Chen, Jiaxin Hu, Pengwei Zhao ...
· Nature cell biology
· Department of Biochemistry and Department of Hepatobiliary and Pancreatic Surgery of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
· pubmed
Ribophagy is a selective autophagic process that regulates ribosome turnover. Although NUFIP1 has been identified as a mammalian receptor for ribophagy, its homologues do not exist in yeast and nematodes. Here we demonstrate that Rpl12, a ribosomal large subunit protein, function...
Ribophagy is a selective autophagic process that regulates ribosome turnover. Although NUFIP1 has been identified as a mammalian receptor for ribophagy, its homologues do not exist in yeast and nematodes. Here we demonstrate that Rpl12, a ribosomal large subunit protein, functions as a conserved ribophagy receptor in multiple organisms. Disruption of Rpl12-Atg8s binding leads to significant accumulation of ribosomal proteins and rRNA, while Atg1-mediated Rpl12 phosphorylation enhances its association with Atg11, thus triggering ribophagy during starvation. Ribophagy deficiency accelerates cell death induced by starvation and pathogen infection, leading to impaired growth and development and a shortened lifespan in both Caenorhabditis elegans and Drosophila melanogaster. Moreover, ribophagy deficiency results in motor impairments associated with ageing, while the overexpression of RPL12 significantly improves movement defects induced by starvation, ageing and Aβ accumulation in fly models. Our findings suggest that Rpl12 functions as a conserved ribophagy receptor vital for ribosome metabolism and cellular homeostasis.
Longevity Relevance Analysis
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Rpl12 functions as a conserved ribophagy receptor that regulates ribosome turnover and impacts lifespan and age-related motor impairments. The study addresses mechanisms of ribophagy that are linked to cellular homeostasis and longevity, suggesting a role in the fundamental processes of aging.
Morris, S., Schmelter, F., Molina Riquelme, I. E. ...
· cell biology
· University of Muenster
· biorxiv
Heart disease is the leading cause of death in the elderly population and the heart is a highly energy-consuming tissue. Aging-related heart failure is often driven by energy depletion in cardiomyocytes (CM), which rely on their abundant, cristae-dense mitochondria for ATP produc...
Heart disease is the leading cause of death in the elderly population and the heart is a highly energy-consuming tissue. Aging-related heart failure is often driven by energy depletion in cardiomyocytes (CM), which rely on their abundant, cristae-dense mitochondria for ATP production. ATP synthase, localized along the cristae rims, plays a critical role in energy conversion, but the connection between its organization and function remains unclear. Here, we explored the spatiotemporal organization of ATP synthase in senescent CM at the level of individual complexes. Using single-molecule localization and tracking microscopy, we observed reduced enzyme mobility within the cristae, coinciding with decreased ATP synthase activity, despite a stable resting mitochondrial membrane potential. This reduction in activity was independent of changes in ATP synthase expression or dimerization. Electron tomography revealed an increased prevalence of curved inner membranes and fenestrated cristae in senescent CM, explaining the reduced enzyme mobility. Senescent CM displayed irregular autonomous and paced beating patterns. These abnormalities suggest that impaired cardiac function is directly driven by disrupted energy metabolism, rooted in the suboptimal organization and function of ATP synthase in altered cristae.
Longevity Relevance Analysis
(4)
The paper claims that impaired cardiac function in senescent cardiomyocytes is driven by disrupted energy metabolism due to altered organization and function of ATP synthase. This research is relevant as it addresses the underlying mechanisms of energy depletion in aging heart cells, which is a critical aspect of age-related heart disease and longevity.
Shohreh Teimuri, Beat Suter
· RNA, Messenger
· Institute of Cell Biology, University of Bern, Berne, Switzerland.
· pubmed
Topoisomerase 3β (Top3β) works not only on DNA but also on RNA. We isolated and identified the naturally cross-linked RNA targets of Drosophila Top3β from an early embryonic stage that contains almost exclusively maternal mRNAs. Favorite targets were long RNAs, particularly with ...
Topoisomerase 3β (Top3β) works not only on DNA but also on RNA. We isolated and identified the naturally cross-linked RNA targets of Drosophila Top3β from an early embryonic stage that contains almost exclusively maternal mRNAs. Favorite targets were long RNAs, particularly with long 3'UTRs, and RNAs that become localized in large cells. Top3β lacking only the hydroxyl group that makes the covalent bond to the RNA, did not allow normal expression and localization of Top3β mRNA targets or their protein products, demonstrating the importance of the enzymatic activity of Top3 β for optimized gene expression. Top3β is not essential for development to the adult stage but to maintain the morphology of the adult neuromuscular junction and to prevent premature loss of coordinated movement and aging. Alterations in human Top3β have been associated with several neurological diseases and cancers. The homologs of genes and (pre)mRNAs mis-expressed in these conditions show the same characteristics identified in the Drosophila Top3β targets, suggesting that Drosophila could model human Top3β. An in vivo test of this model showed that the enzymatic activity of Top3β reduces the neurodegeneration caused by the cytotoxic human (G4C2)49 RNA. Top3β supports normal gene expression, particularly of long and complex transcripts that must be transported and translationally controlled. These RNAs encode large cytoskeletal, cortical, and membrane proteins that are particularly important in large and long cells like motoneurons. Their reduced expression in the mutant seems to stress the cells, increasing the chances of developing neurodegenerative diseases.
Longevity Relevance Analysis
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The paper claims that Drosophila Topoisomerase 3β contributes to mRNA localization and stability, which in turn counteracts premature aging. The research is relevant as it explores a potential mechanism underlying aging processes and neurodegeneration, suggesting a role for Top3β in maintaining cellular health and longevity.
Liu, H., Yuan, L., GV, S.
· cell biology
· ETH Zurich and Paul Scherrer Institut
· biorxiv
Robust 3D tissue culture models to activate aged fibroblasts for cell-based therapies and identify regulators of such activation are still missing. In our previous study, we showed that aged fibroblasts can be activated simply through applying compressive force, without the need ...
Robust 3D tissue culture models to activate aged fibroblasts for cell-based therapies and identify regulators of such activation are still missing. In our previous study, we showed that aged fibroblasts can be activated simply through applying compressive force, without the need for exogenous factors, leading to increased migration. In this study, we develop a pipeline to evaluate the role of specific pharmacological inhibitors for transcription factor inference and cell migration involved in aged fibroblast activation. By integrating RNA-seq data with bioinformatic tools (prize collecting Steiner tree method and iRegulon) we inferred 15 candidates. In addition, we used cell migration and heterochromatin content as readouts for validating these candidates. Furthermore, we identified three potential master regulators of fibroblast activation and rejuvenation: FOXO1, STAT3, and PDK1. These findings offer valuable insights for future drug discovery, disease modeling, and regenerative medicine.
Longevity Relevance Analysis
(4)
The study identifies potential master regulators of aged fibroblast activation that could inform future drug discovery and regenerative medicine approaches. The focus on understanding and potentially reversing cellular aging mechanisms in fibroblasts aligns with longevity research goals.
Min Li, Bo Chen, Sibo Sun ...
· Cell proliferation
· Department of Geriatrics, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
· pubmed
Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation and senescence. Previous studies showed that club cells and club cell secretory proteins (CCSP) have anti-inflammatory roles, which reduced in COPD. Klotho (KL) decreased in human COPD lung tiss...
Chronic obstructive pulmonary disease (COPD) is characterised by chronic inflammation and senescence. Previous studies showed that club cells and club cell secretory proteins (CCSP) have anti-inflammatory roles, which reduced in COPD. Klotho (KL) decreased in human COPD lung tissue. KL-deficient mice showed aging phenotypes, such as obvious emphysema and premature senility at the early stage, which are characteristics of COPD. However, little is known about the relationship between KL, club cells, and COPD. We speculated lack of KL would aggravate club cell senescence, which contributes to COPD inflammation. We collected COPD lung tissue using single-cell RNA sequencing (scRNA-seq), revealing club cells heterogeneity and cellular senescence in COPD. In addition, KL and CCSP expressions were downregulated in cigarette smoke (CS)-induced COPD mice, associated with increasing age-related markers. After KL knockout, more ciliated cells appeared where club cells disappeared. Furthermore, KL deficiency aggravated club cell senescence and CSE-induced pulmonary inflammation. To investigate the specific regulation mechanism, hnRNPA2/B1 was recognised and identified it was the key molecule in KL-regulated club cell senescence, and neddylation of club cell was a crucial factor contributing to hnRNPA2/B1 downregulation. In vitro, SA-β-gal staining suggested the aging phenotype was aggravated in hnRNPA2/B1-silenced groups, and hnRNPA2/B1 over-expressed achieved a rescue result. Thus, KL could regulate club cell senescence and differentiation. When CS stimulates the small airway epithelium, KL deficiency aggravates lung inflammation, club cell senescence and dysfunctional of ciliated cell. Targeting neddylation might be a promising strategy to reverse lung aging and club cell senescence. These results provide a mechanism about COPD-linked lung inflammation.
Longevity Relevance Analysis
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Klotho deficiency aggravates club cell senescence and inflammation in COPD, suggesting a potential mechanism linking aging and lung disease. The study addresses the role of Klotho in cellular senescence, which is a key aspect of aging and age-related diseases, making it relevant to longevity research.
He, X., Zhang, H., Wang, Y. ...
· developmental biology
· State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Clinical Reproductive Medicine, the First Affiliated Hospital of Nanjing Medical
· biorxiv
The decline in oocytes quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, through an integrative analysis of transcriptomes and morphologies of individual oocytes ...
The decline in oocytes quality and developmental potential with female reproductive aging is well recognized, yet the underlying mechanisms remain insufficiently investigated. In this study, through an integrative analysis of transcriptomes and morphologies of individual oocytes from young and aged mice, morphologically defective aged oocytes are identified with distinct transcriptomic features. Further analysis demonstrates that both apoptotic and ferroptotic pathways are activated in the defective aged oocytes, and simultaneously blocking both pathways reverses the defective morphology to the largest extent. The Plat gene, which encodes tissue-type plasminogen activator (tPA), is downregulated with oocyte aging, and Plat knockdown increases oocytes susceptibility to both apoptosis and ferroptosis. Mechanistically, tPA functions as an upstream signaling molecule for Erk1/2 activation by interacting with particular phosphorylation kinases such as Alk. Consequently, Plat loss downregulates Erk1/2 pathway activity in oocytes, leading to degeneration through programmed cell death. Supplementing exogenous tPA in in vitro oocyte maturation cultures reduces defect rate of aged oocytes, thereby improving oocyte quality and developmental potential. Collectively, Plat plays a pivotal role in protecting aged mouse oocytes from programmed cell death, and tPA supplementation may serve as a potential clinical strategy to enhance oocyte quality in females of advanced maternal age.
Longevity Relevance Analysis
(4)
The paper claims that the Plat gene protects aged mouse oocytes from programmed cell death by activating the Erk1/2 pathway, and that tPA supplementation can improve oocyte quality in older females. This research addresses mechanisms underlying reproductive aging, which is a significant aspect of longevity and age-related decline in fertility.
Goldberg, D. C., Cloud, C., Lee, S. M. ...
· genomics
· Children\\\'s Hospital of Philadelphia
· biorxiv
Epigenome-wide association studies (EWAS) are transforming our understanding of the interplay between epigenetics and complex human traits and phenotypes. We introduce the Methylation Screening Array (MSA), a new iteration of the Infinium technology for scalable and quantitative ...
Epigenome-wide association studies (EWAS) are transforming our understanding of the interplay between epigenetics and complex human traits and phenotypes. We introduce the Methylation Screening Array (MSA), a new iteration of the Infinium technology for scalable and quantitative screening of trait associations of nuanced ternary-code cytosine modifications in larger, more inclusive, and stratified human populations. MSA integrates EWAS, single-cell, and cell-type-resolved methylome profiles, covering diverse human traits and diseases. Our first MSA applications yield multiple biological insights: we revealed a previously unappreciated role of 5-hydroxymethylcytosine (5hmC) in trait associations and epigenetic clocks. We demonstrated that 5hmCs complement 5-methylcytosines (5mCs) in defining tissues and cells' epigenetic identities. In-depth analyses highlighted the cell type context of EWAS and GWAS hits. Using this platform, we conducted a comprehensive human 5hmC aging EWAS, discovering tissue-invariant and tissue-specific aging dynamics, including distinct tissue-specific rates of mitotic hyper- and hypomethylation rates. These findings chart a landscape of the complex interplay of the two forms of cytosine modifications in diverse human tissues and their roles in health and disease.
Longevity Relevance Analysis
(4)
The paper claims to reveal the role of 5-hydroxymethylcytosine in aging dynamics and epigenetic identities across human tissues. The research explores the epigenetic mechanisms underlying aging, which is directly relevant to understanding the biological processes of longevity and age-related changes.
Henriette Thau, Bastian P Gerjol, Katharina Hahn ...
· Skin Aging
· Van Cleve Cardiac Regenerative Medicine Program Mayo Clinic, Rochester, Minesota, USA; Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum der Charité (DHZC), Berlin, Germany; Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
· pubmed
Skin aging represents a multifactorial process influenced by both intrinsic and extrinsic factors, collectively known as the skin exposome. Cellular senescence, characterized by stable cell cycle arrest and secretion of pro-inflammatory molecules, has been implicated as a key dri...
Skin aging represents a multifactorial process influenced by both intrinsic and extrinsic factors, collectively known as the skin exposome. Cellular senescence, characterized by stable cell cycle arrest and secretion of pro-inflammatory molecules, has been implicated as a key driver of physiological and pathological skin aging. Increasing evidence points towards the role of senescence in a variety of dermatological diseases, where the accumulation of senescent cells in the epidermis and dermis exacerbates disease progression. Emerging therapeutic strategies such as senolytics and senomorphics offer promising avenues to target senescent cells and mitigate their deleterious effects, providing potential treatments for both skin aging and senescence-associated skin diseases. This review explores the molecular mechanisms of cellular senescence and its role in promoting age-related skin changes and pathologies, while compiling the observed effects of senotherapeutics in the skin and discussing the translational relevance.
Longevity Relevance Analysis
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Cellular senescence is a key driver of skin aging and associated diseases, and targeting it with senotherapeutics may mitigate these effects. The paper addresses the root causes of aging by exploring cellular senescence and potential therapeutic strategies, making it relevant to longevity research.
Li, Y., Goodrich, J. M., Peterson, K. E. ...
· epidemiology
· Rutgers- The State University of New Jersey (All Campuses)
· medrxiv
DNA methylation (DNAm) is a chemical modification of DNA that can be influenced by various factors, including age, environment, and lifestyle. An epigenetic clock is a predictive tool that measures biological age based on DNAm levels. It can provide insights into an individual's ...
DNA methylation (DNAm) is a chemical modification of DNA that can be influenced by various factors, including age, environment, and lifestyle. An epigenetic clock is a predictive tool that measures biological age based on DNAm levels. It can provide insights into an individual's biological age, which may differ from their chronological age. This difference, known as the epigenetic age acceleration, may indicate the state of one's health and risk for age-related diseases. Moreover, epigenetic clocks are used in studies of aging to assess the effectiveness of anti-aging interventions and to understand the underlying mechanisms of aging and disease. Various epigenetic clocks have been developed using samples from different populations, tissues, and cell types, typically by training high-dimensional linear regression models with an elastic net penalty. While these models can predict mean biological age with high precision, there is a lack of uncertainty quantification which is important for interpreting the precision of age estimations and for clinical decision-making. To understand the distribution of a biological age clock beyond its mean, we propose a general pipeline for training epigenetic clocks, based on an integration of high-dimensional quantile regression and conformal prediction, to effectively reveal population heterogeneity and construct prediction intervals. Our approach produces adaptive prediction intervals not only achieving nominal coverage but also accounting for the inherent variability across individuals. By using the data collected from 728 blood samples in 11 DNAm datasets from children, we find that our quantile regression-based prediction intervals are narrower than those derived from conventional mean regression-based epigenetic clocks. This observation demonstrates an improved statistical efficiency over the existing pipeline for training epigenetic clocks. In addition, the resulting intervals have a synchronized varying pattern to age acceleration, effectively revealing cellular evolutionary heterogeneity in age patterns in different developmental stages during individual childhoods and adolescent cohort. Our findings suggest that conformalized high-dimensional quantile regression can produce valid prediction intervals and uncover underlying population heterogeneity. Although our methodology focuses on the distribution of aging in children, it is applicable to a broader range of populations to improve understanding of epigenetic age beyond the mean. This inference-based toolbox could provide valuable insights for future applications of epigenetic interventions for age-related diseases.
Longevity Relevance Analysis
(4)
The paper claims that conformalized high-dimensional quantile regression can produce valid prediction intervals for epigenetic clocks, revealing population heterogeneity in biological aging. This research is relevant as it addresses the quantification of biological age, which is crucial for understanding aging mechanisms and potential interventions for age-related diseases.
Fang Yu, Changhan Chen, Wuping Liu ...
· Aging cell
· Department of Neurology, Central South University, Changsha, China.
· pubmed
Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity i...
Longevity individuals have lower susceptibility to chronic hypoxia, inflammation, oxidative stress, and aging-related diseases. It has long been speculated that "rejuvenation molecules" exist in their blood to promote extended lifespan. We unexpectedly discovered that longevity individuals exhibit erythrocyte oxygen release function similar to young individuals, whereas most elderly show reduced oxygen release capacity. Untargeted erythrocyte metabolomics profiling revealed that longevity individuals are characterized by youth-like metabolic reprogramming and these metabolites effectively differentiate the longevity from the elderly. Quantification analyses led us to identify multiple novel longevity-related metabolites within erythrocytes including adenosine, sphingosine-1-phosphate (S1P), and glutathione (GSH) related amino acids. Mechanistically, we revealed that increased bisphosphoglycerate mutase (BPGM) and reduced MFSD2B protein levels in the erythrocytes of longevity individuals collaboratively work together to induce elevation of intracellular S1P, promote the release of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from membrane to the cytosol, and thereby orchestrate glucose metabolic reprogramming toward Rapoport-Luebering Shunt to induce the 2,3-BPG production and trigger oxygen delivery. Furthermore, increased glutamine and glutamate transporter expression coupled with the enhanced intracellular metabolism underlie the elevated GSH production and the higher anti-oxidative stress capacity in the erythrocytes of longevity individuals. As such, longevity individuals displayed less systemic hypoxia-related metabolites and more antioxidative and anti-inflammatory metabolites in the plasma, thereby healthier clinical outcomes including lower inflammation parameters as well as better glucose-lipid metabolism, and liver and kidney function. Overall, we identified that youthful erythrocyte function and metabolism enable longevity individuals to better counteract peripheral tissue hypoxia, inflammation, and oxidative stress, thus maintaining healthspan.
Longevity Relevance Analysis
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The paper claims that youthful erythrocyte function and metabolic signatures in longevity individuals help them better counteract hypoxia, inflammation, and oxidative stress, thereby maintaining healthspan. This research addresses mechanisms underlying aging and longevity, focusing on metabolic reprogramming and cellular function, which are central to understanding and potentially mitigating the root causes of aging.
Doherty, T., McDermott, E., Delany, S. J. ...
· bioinformatics
· Technological University Dublin
· biorxiv
Background: Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a dysregulated immune response partly influenced by environmental factors. DNA methylation (DNAm), a key epigenetic mechanism, is implicated in the etiology of complex diseases, including IBD. ...
Background: Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a dysregulated immune response partly influenced by environmental factors. DNA methylation (DNAm), a key epigenetic mechanism, is implicated in the etiology of complex diseases, including IBD. Epigenetic clocks, which use DNAm patterns to estimate biological aging, have been increasingly linked to various health and disease states. Previous studies have associated DNAm with IBD, and first- and second-generation epigenetic clocks with IBD subtypes. Results: In a discovery IBD cohort (n=149) with 8-year clinical follow-up data, we explored the relationship between DNAm variation, second- and third-generation epigenetic clocks, and IBD clinicopathological outcomes, including disease subtype, activity, and recurrence. One CpG site was significantly differentially methylated (Benjamini-Hochberg adjusted p-value<0.05) in patients with clinical recurrence of disease over the long term (i.e., after the first year of study) compared to non-recurrence (no treatment escalation after 8 years). Next, we assessed DNAm aging signatures and IBD outcomes using logistic regression. Individuals with IBD exhibited significantly increased epigenetic aging, as measured by GrimAge, GrimAge2, and DunedinPACE, compared with controls. These associations were replicated in two independent IBD cohorts (GSE87648 (n=377) and GSE112611 (n=238)). Additionally, in UC patients, the active disease group was associated with higher age acceleration (GrimAge (U=669, p=0.003)) and higher pace of aging (DunedinPACE (t=3.233, 0.002)) compared to the inactive group. In the discovery cohort, DunedinPACE outperforms CRP measures in discriminating activity in UC patients with an AUC, sensitivity and specificity of 0.71, 69.5% and 68.7% respectively, highlighting its potential as a useful biomarker of activity in UC. Conclusions: Overall, we present strong evidence that dynamic age-related DNAm changes can be used to differentiate between IBD (including separately by subtype) and controls. Furthermore, our study provides important new evidence that DunedinPACE may have utility as a biomarker for monitoring disease recurrence in IBD patients and may be a strong marker of disease activity in UC patients. Overall, this suggests that blood-based DNAm signatures could serve as biomarkers for detection and monitoring of IBD.
Longevity Relevance Analysis
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The study claims that blood-based DNA methylation signatures can differentiate between IBD patients and controls, and may serve as biomarkers for disease activity and recurrence. This research is relevant as it explores the relationship between epigenetic aging and disease progression, contributing to the understanding of aging mechanisms in the context of chronic diseases.
Qiaowei Li, Qin Liu, Zhong Lin ...
· The journals of gerontology. Series A, Biological sciences and medical sciences
· Shengli Clinical Medical College of Fujian Medical University, Fuzhou, P.R.China.
· pubmed
The impact of mid-late-life exercise on the aging heart remains unclear, particularly the effects of high-intensity interval training (HIIT) and continuous moderate-intensity training (CMIT). This study was the first to examine cardiac function, tissue characteristics, electrical...
The impact of mid-late-life exercise on the aging heart remains unclear, particularly the effects of high-intensity interval training (HIIT) and continuous moderate-intensity training (CMIT). This study was the first to examine cardiac function, tissue characteristics, electrical remodeling, mitochondrial morphology and homeostasis in old mice subjected to CMIT or HIIT, compared to untrained controls. Our results showed that 8-week HIIT significantly improved the survival rate of old mice. HIIT presented advantages on cardiac function, deposition of collagen fibers, neovascularization, aging biomarkers and mitochondrial homeostasis. Only CMIT alleviated age-related cardiac hypertrophy. However, CMIT potentially exacerbated adverse cardiac electrical remodeling. Those findings suggested HIIT as a particularly appealing option for clinical application for aging populations.
Longevity Relevance Analysis
(4)
High-intensity interval training (HIIT) improves cardiac function and survival rates in aging mice compared to continuous moderate-intensity training (CMIT). This study addresses the effects of exercise on aging-related cardiac function, which is crucial for understanding interventions that may mitigate age-related decline.
Ye, Q., Ahamed, A., Shalev, I. ...
· obstetrics and gynecology
· Duke University
· medrxiv
Evolutionary theories of aging indicate trade-offs between reproduction and longevity. Epigenetic clocks, such as PhenoAge, GrimAge, and DunedinPoAm, were designed to reflect biological age and be used as surrogates for mortality and healthspan. The current study investigated the...
Evolutionary theories of aging indicate trade-offs between reproduction and longevity. Epigenetic clocks, such as PhenoAge, GrimAge, and DunedinPoAm, were designed to reflect biological age and be used as surrogates for mortality and healthspan. The current study investigated the connection between reproductive profiles, epigenetic aging, and mortality among post-menopausal women (50-85 years) with data from the National Health and Nutrition Examination Survey across the United States (N=770). Using latent profile analysis, we identified four distinct reproductive profiles: high gravidity but average parity (Class 1); high gravidity and parity (Class 2); early menopause (Class 3); and an average profile (Class 4). Women of Class 3 had an accelerated pace of aging as indicated by DunedinPoAm, but not an older epigenetic age as measured by PhenoAge or GrimAge. The association was significant among women who had ever used female hormones ({beta}=0.521; 95%CI 0.014-1.027). Women of Class 1 or 2 did not exhibit accelerated epigenetic aging. Women of Class 3 had higher mortality (HR=1.40, 95%CI 1.08-1.81), and 36.3% of the effect was mediated through accelerated DunedinPoAm. Findings suggest that women with reproductive profiles characterized by early menopause may have altered epigenetic aging trajectories. Pace of aging may be more sensitive to the impact of reproductive profile variations than the status of biological age as indicated by PhenoAge or GrimAge. Clinically monitoring the pace of biological aging among women with early menopause and an appropriate application of hormone replacement therapy may minimize the negative consequence of accelerated biological aging and reduce premature mortality.
Longevity Relevance Analysis
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The paper claims that women with reproductive profiles characterized by early menopause may experience accelerated biological aging and higher mortality rates. This research is relevant as it explores the relationship between reproductive factors and biological aging, potentially addressing underlying mechanisms that influence longevity and healthspan in post-menopausal women.
Manish Kumar, Abhishek Singh Sengar, Anushree Lye ...
· Reactive Oxygen Species
· Centre of Biomedical Research, Raebareli Road, Lucknow, Uttar Pradesh, 226014, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad-201002, India.
· pubmed
Cardiotoxicity remains a major limiting factor in the clinical implementation of anthracycline chemotherapy. Though the etiology of doxorubicin-dependent heart damage has yet to be fully elucidated, the ability of doxorubicin to damage DNA and trigger oxidative stress have been h...
Cardiotoxicity remains a major limiting factor in the clinical implementation of anthracycline chemotherapy. Though the etiology of doxorubicin-dependent heart damage has yet to be fully elucidated, the ability of doxorubicin to damage DNA and trigger oxidative stress have been heavily implicated in the pathogenesis of chemotherapy-associated cardiomyopathy. Here, we demonstrate that fibronectin type III domain-containing protein 5 (FNDC5), the precursor protein for myokine irisin, is depleted in the hearts of human cancer patients or mice exposed to chemotherapeutics. In cardiomyocytes, restoration of FNDC5 expression was sufficient to mitigate reactive oxygen species (ROS) accumulation and apoptosis following doxorubicin exposure, effects dependent on the irisin encoding domain of FNDC5 as well as signaling via the putative irisin integrin receptor. Intriguingly, we identified two parallel signaling cascades impacted by FNDC5 in cardiomyocytes: the ROS-driven intrinsic mitochondrial apoptosis pathway and the ROS-independent Ataxia Telangiectasia and Rad3-Related Protein (ATR)/Checkpoint Kinase 1 (Chk1) pathway. In fact, FNDC5 forms a co-precipitable complex with Chk1 alluding to possible intracellular actions for this canonically membrane-associated protein. Whereas FNDC5 overexpression in murine heart was cardioprotective, introduction of FNDC5-targeted shRNA into the myocardium was sufficient to trigger Bax up-regulation, ATR/Chk1 activation, oxidative stress, cardiac fibrosis, loss of ventricular function, and compromised animal survival. The detrimental impact of FNDC5 depletion on heart function could be mitigated via treatment with a Chk1 inhibitor identifying Chk1 hyperactivity as a causative factor in cardiac disease. Though our data point to the potential clinical utility of FNDC5/irisin-targeted agents in the treatment of chemotherapy-induced cardiotoxicity, we also found significant down regulation in FNDC5 expression in the hearts of aged mice that attenuated the cardioprotective impacts of FNDC5 overexpression following doxorubicin exposure. Together our data underscore the importance of FNDC5/irisin in maintenance of cardiac health over the lifespan.
Longevity Relevance Analysis
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The paper claims that FNDC5/irisin can mitigate cardiotoxicity from chemotherapy by modulating oxidative stress pathways. The research addresses a mechanism that could contribute to cardiac health and longevity, particularly in the context of aging and the effects of chemotherapy on the heart.
Takayasu, L., Watanabe, E., Umeyama, T. ...
· microbiology
· RIKEN
· biorxiv
The temporal changes of the gut microbiome are thought to be critical for understanding its interactions with host aging, but lifelong dynamics within the same individual remain largely unknown. Here we firstly report the high temporal resolution dynamics of gut microbiomes in mi...
The temporal changes of the gut microbiome are thought to be critical for understanding its interactions with host aging, but lifelong dynamics within the same individual remain largely unknown. Here we firstly report the high temporal resolution dynamics of gut microbiomes in mice sharing the same genetic background and environment from their birth to natural death, spanning >1,000 days. The 16S rRNA sequencing analysis revealed 9 patterns of OTU temporal dynamics and 38 common ''life-core'' bacterial species/operational taxonomic units (OTUs) in [≥]80% of all samples across the lifespan of individual mice. The life-core OTUs are largely represented by the phylum Bacteroidota, whereas the transient bacterial group predominantly includes the phylum Firmicutes (Bacillota). Despite the shared genetic background and dietary habits, the gut microbiome structure significantly diversified with age and among individuals. A positive correlation existed between longevity and the microbiome -diversity in middle age (200-500 days) followed by a negative correlation in old age (>700 days), likely influenced by the increase in diversity during the last days of life. The abundance of several ''life-core'' species also exhibited non-static correlation trends with lifespan. Overall, this research characterized the gut microbiomes based on its persistence over host's lifetime and suggested a non-static host-microbiome relationship within individual mice.
Longevity Relevance Analysis
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The paper claims that the gut microbiome exhibits non-static dynamics throughout the lifespan of mice, with correlations between microbiome diversity and longevity. This research is relevant as it explores the relationship between gut microbiome changes and aging, potentially shedding light on mechanisms that influence longevity and the aging process.
Strzelczyk, D., Peylo, C., Langer, N.
· neuroscience
· University of Zurich
· biorxiv
Aging is associated with cognitive decline and memory impairment, but the underlying neural mechanisms remain unclear. Phase-amplitude coupling (PAC) between mid-frontal theta (5 Hz) and occipital gamma (>30 Hz) oscillations is a proposed marker for parallel storage of multiple i...
Aging is associated with cognitive decline and memory impairment, but the underlying neural mechanisms remain unclear. Phase-amplitude coupling (PAC) between mid-frontal theta (5 Hz) and occipital gamma (>30 Hz) oscillations is a proposed marker for parallel storage of multiple items in working memory. However, research has mainly focused on young individuals and epilepsy patients, with only a few studies on aging populations. Moreover, these studies have relied on univariate PAC methods, which can be flawed by potential spurious or biased PAC estimates due to non-stationarity of EEG signals. Additionally, these methods typically assess PAC at the level of individual electrodes, potentially overlooking the broader functional significance of theta-gamma coupling in coordinating neural activity across distant brain regions. To address these gaps, we employed multivariate PAC (mPAC) through generalized eigendecomposition (GED) analysis, which avoids the pitfalls of non-sinusoidal oscillations. 113 young and 117 older healthy participants engaged in a sequence learning paradigm (6423 sequence repetitions, 55\'944 stimuli), in which they learned a fixed sequence of visual stimuli over repeated observations, allowing us to track the mPAC during the incremental process of learning. Behavioral results revealed that younger participants learned significantly faster than older participants. Neurophysiological data showed that mPAC increased over the course of learning in both age groups and could identify fast and slow learners. However, older participants exhibited lower mPAC compared to younger counterparts, which suggest compromised parallel storage of items in working memory in older age. Finally, stratification analysis revealed that mPAC effects persist across performance groups with similar mid-frontal theta levels, suggesting that theta alone does not account for these effects. These findings shed light on the age-related differences in memory formation processes and may guide interventions to enhance memory performance in older adults and slow learners.
Longevity Relevance Analysis
(4)
Older adults exhibit lower multivariate phase-amplitude coupling during learning compared to younger individuals, indicating compromised memory processes. The study addresses cognitive decline in aging, focusing on neural mechanisms that could inform interventions to enhance memory performance in older adults, thus contributing to understanding the aging process.
Sabira Mohammed, Phoebe Ohene-Marfo, Chao Jiang ...
· GeroScience
· Stephenson Cancer Center, Department of Biochemistry and Physiology, Oklahoma Center for Geroscience & Brain Aging, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA.
· pubmed
Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases wit...
Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases with age and contributes to morbidity and mortality among the elderly. This study investigates the role of necroptosis, a programmed cell death pathway that promotes inflammation, in liver inflammaging and age-associated MASLD by utilizing genetic ablation models of two key necroptosis proteins, Mlkl or Ripk3. The absence of Mlkl or Ripk3 significantly reduced liver inflammation, steatosis, and fibrosis in aged male mice, supporting the role of necroptosis in age-associated MASLD. Additionally, Mlkl or Ripk3 deletion impacted other non-necroptotic cellular processes that drive inflammation and MASLD, such as cellular senescence, apoptosis, and autophagy in aged liver. Levels of plasma TNFα and IL6, key proinflammatory cytokines associated with inflammaging, are reduced in Mlkl
Longevity Relevance Analysis
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The paper claims that the deletion of Mlkl or Ripk3 reduces liver inflammation and metabolic dysfunction associated with aging. This research addresses the mechanisms of inflammation and necroptosis in the context of aging and age-related diseases, which are critical for understanding and potentially mitigating the root causes of aging.
Tayler N LaSharr, Samantha P H Dwinnell, Rhiannon P Jakopak ...
· Reproduction
· Haub School of Environment and Natural Resources, University of Wyoming, Bim Kendall House, 804 E Fremont St., Laramie, WY, 82072, USA. [email protected].
· pubmed
Deterioration in nutritional condition with aging could reduce reproductive success but coincides with declines in residual reproductive potential, thus invoking opposing expectations for late-life reproduction. Yet, the mechanisms regulating energy accrual and allocation to repr...
Deterioration in nutritional condition with aging could reduce reproductive success but coincides with declines in residual reproductive potential, thus invoking opposing expectations for late-life reproduction. Yet, the mechanisms regulating energy accrual and allocation to reproduction and survival throughout the lifetime of long-lived, iteroparous animals have remained elusive owing to variation in energetic costs across their extended reproductive cycle (from conception to juvenile independence). Using 10 years of repeated measures of both nutrition (i.e., body fat and food availability) and reproductive allocation across the reproductive cycle of 232 free-ranging, adult, female mule deer, we revealed that nutrition is a critical piece in understanding patterns of reproductive senescence and terminal investment. From conception to weaning, age-related patterns of reproduction were influenced by both body fat and environmental conditions. Reproductive senescence was clear across the entire reproductive cycle, although allocation to offspring was partly mediated by nutrition. Terminal investment, however, was most evident towards the end of the annual reproductive cycle and unveiled only when considering nutritional condition and food availability; during years with poor resource availability, older mothers raised larger juveniles (i.e., 6-months old). Our work evokes nutrition as a lurking variable in end-of-life reproductive tactics for long-lived animals, while demonstrating the necessity of accounting for energy when considering patterns of reproductive senescence and terminal investment in wild animals.
Longevity Relevance Analysis
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Nutrition influences reproductive senescence and terminal investment in long-lived mammals. The study addresses how nutritional factors affect reproductive strategies and aging in wild animals, contributing to the understanding of longevity and reproductive success in the context of aging.
Patricia L Opresko, Samantha L Sanford, Mariarosaria De Rosa
· Cold Spring Harbor perspectives in biology
· Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA [email protected].
· pubmed
Oxidative stress is associated with increasing telomere shortening and telomere dysfunction, as well as with numerous pathologies in humans, including inflammatory diseases and cancer. Critically short and dysfunctional telomeres lose their ability to protect chromosome ends, whi...
Oxidative stress is associated with increasing telomere shortening and telomere dysfunction, as well as with numerous pathologies in humans, including inflammatory diseases and cancer. Critically short and dysfunctional telomeres lose their ability to protect chromosome ends, which triggers irreversible growth arrest, termed senescence, or genomic instability. Telomeres are highly sensitive to damage from reactive oxygen species, which increase under conditions of oxidative stress. This work covers the evidence that oxidative damage to telomeric DNA alters telomere maintenance by various mechanisms and describes the DNA repair pathways important for preserving telomere function under oxidative stress conditions.
Longevity Relevance Analysis
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Oxidative stress contributes to telomere shortening and dysfunction, impacting cellular senescence and genomic stability. The paper is relevant as it addresses mechanisms that could influence the aging process by focusing on telomere maintenance, which is a critical factor in longevity and age-related diseases.
Quetzalli D Angeles-Lopez, Jhonny Rodriguez-Lopez, Paula Agudelo Garcia ...
· Fatty Acids
· Department of Internal Medicine, Division of Pulmonary Critical Care and Sleep Medicine, The Ohio State University, Columbus, Ohio, USA.
· pubmed
Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in a...
Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease, characterized by inadequate alveolar regeneration and ectopic bronchiolization. While some molecular pathways regulating lung progenitor cells have been described, the role of metabolic pathways in alveolar regeneration is poorly understood. We report that expression of fatty acid oxidation (FAO) genes is significantly diminished in alveolar epithelial cells of IPF lungs by single-cell RNA sequencing and tissue staining. Genetic and pharmacological inhibition in AT2 cells of carnitine palmitoyltransferase 1a (CPT1a), the rate-limiting enzyme of FAO, promoted mitochondrial dysfunction and acquisition of aberrant intermediate states expressing basaloid, and airway secretory cell markers SCGB1A1 and SCGB3A2. Furthermore, mice with deficiency of CPT1a in AT2 cells show enhanced susceptibility to developing lung fibrosis with an accumulation of epithelial cells expressing markers of intermediate cells, airway secretory cells, and senescence. We found that deficiency of CPT1a causes a decrease in SMAD7 protein levels and TGF-β signaling pathway activation. These findings suggest that the mitochondrial FAO metabolic pathway contributes to the regulation of lung progenitor cell repair responses and deficiency of FAO contributes to aberrant lung repair and the development of lung fibrosis.
Longevity Relevance Analysis
(4)
The paper claims that mitochondrial fatty acid oxidation is crucial for the regulation of lung progenitor cell repair responses and that its deficiency contributes to lung fibrosis. This research is relevant as it explores metabolic pathways that may influence aging-related lung diseases, potentially addressing root causes of age-related decline in lung function.
Jiasheng Wang, Peng Guo, Dongmei Wu ...
· Advanced science (Weinheim, Baden-Wurttemberg, Germany)
· Department of Sports Medicine of the Second Affiliated Hospital, and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, 310058, China.
· pubmed
Osteoarthritis (OA) is one of the most common joint degenerative diseases without effective treatment, whose pathology is related to the local accumulation of senescent cells (SnCs). However, existing SnCs-scavenging drugs "senolytics" may lead to the exhaustion of stem and proge...
Osteoarthritis (OA) is one of the most common joint degenerative diseases without effective treatment, whose pathology is related to the local accumulation of senescent cells (SnCs). However, existing SnCs-scavenging drugs "senolytics" may lead to the exhaustion of stem and progenitor cells, impairing chondrocyte proliferation and cartilage regeneration. Here, ADAM19, a kind of endopeptidases from the ADAM (a disintegrin and metalloproteinase) family, is identified as a novel target for senescent chondrocyte rejuvenation. ADAM19 is elevated in senescent chondrocytes in both mice and human osteoarthritic joints, as well as in cellular senescence model in vitro. ADAM19 knockdown not only significantly attenuated senescent phenotype of chondrocytes, but also promoted cell proliferation and extracellular matrix synthesis. RNA sequencing revealed ADAM19 may regulate chondrocyte senescence mainly through the PI3K/AKT signal axis. In addition, a senescence-targeting small interfering RNA (siRNA) delivery system is developed for in vivo delivery of therapeutic siRNA. The complex selectively released ADAM19 siRNA in SnCs and performed high silencing effect on target gene. Furthermore, intra-articular (IA) injection of the complex once every two weeks in OA mice effectively reduced SnCs accumulation and promoted hyaline cartilage regeneration. This study provides a promising strategy for the development of regenerative RNA interference therapy.
Longevity Relevance Analysis
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The paper claims that targeting ADAM19 can rejuvenate senescent chondrocytes and promote cartilage regeneration in osteoarthritis. This research is relevant as it addresses the underlying mechanisms of cellular senescence, which is a significant contributor to aging and age-related diseases, potentially offering a novel therapeutic approach to mitigate the effects of aging on joint health.
Nadour, M., LEATIS, R. I. V. R., BIARD, M. ...
· developmental biology
· UQAM
· biorxiv
Neuronal architecture established embryonically must persist lifelong to ensure normal brain function. However, little is understood about the mechanisms behind the long-term maintenance of neuronal organization. To uncover maintenance mechanisms, we performed a suppressor screen...
Neuronal architecture established embryonically must persist lifelong to ensure normal brain function. However, little is understood about the mechanisms behind the long-term maintenance of neuronal organization. To uncover maintenance mechanisms, we performed a suppressor screen in sax-7/L1CAM mutants, which exhibit progressive disorganization with age. We identified the conserved extracellular matrix protein MIG-6/papilin as a key regulator of neuronal maintenance. Combining incisive molecular genetics, structural predictions, in vivo quantitative imaging, and cutting-edge Brillouin microscopy, we show that MIG-6/papilin remodels extracellular matrix collagen IV, working in concert with the secreted enzymes MIG-17/ADAMTS and PXN-2/peroxidasin. This remodeling impacts tissue biomechanics and ensures neuronal stability, even under increased mechanical stress. Our findings highlight an extracellular mechanism by which MIG-6/papilin supports the integrity of neuronal architecture throughout life. This work provides critical insights into the molecular basis of sustaining neuronal architecture and offers a foundation for understanding age-related and neurodegenerative disorders.
Longevity Relevance Analysis
(4)
MIG-6/papilin remodels extracellular matrix collagen IV to maintain neuronal architecture throughout life. This research addresses mechanisms that contribute to the long-term maintenance of neuronal organization, which is crucial for understanding age-related neurodegenerative disorders and the biological processes underlying aging.
Falcsik, G., Keresztes, F., Balod, T. M. ...
· genetics
· Department of Genetics, Eotvos Lorand University (ELTE), Budapest, Hungary
· biorxiv
Macroautophagy (hereafter referred to as autophagy) is an important self-renewal process in our cells, whereby potentially harmful cellular components are encapsulated within a double-membrane autophagosome and subsequently fused with a lysosome for degradation by acidic hydrolas...
Macroautophagy (hereafter referred to as autophagy) is an important self-renewal process in our cells, whereby potentially harmful cellular components are encapsulated within a double-membrane autophagosome and subsequently fused with a lysosome for degradation by acidic hydrolases. This lysosomal degradation process is essential for maintaining cellular homeostasis. Dysfunctional autophagy can lead to the accumulation of cytotoxic protein forms that contribute to the onset of age-related diseases. However, it has been proven that autophagy activity declines with age so it is therefore particularly important to stimulate autophagy during the lifespan of post-mitotic cells, such as neurons, where cell division is not a possibility in order to replace dead cells. Our research group aims to find new autophagy activation sites to stimulate the efficiency of acid degradation in neurons during ageing. One possibility is the stimulation of membrane fusion events, which are necessary for autophagic degradation, through the activation of small GTPase enzymes. Our previous results have shown that neuron-specific overexpression of the activated form of the Rab2 small GTPase has autophagy and lifespan-enhancing effects. In the present experiment, we used an RNA interference screen to investigate whether silencing 12 GTPase-activating proteins (GAPs) belonging to the TBC1 domain family can enhance Rab2 activation in the Drosophila nervous system. Several of the GAPs studied increased the number of Rab2-positive structures, 5 of which were selected for further screening. Our results suggest that neuronal silencing of CG42795 exerts an effect on autophagy, with the capacity to enhance the locomotor ability of animals and prolong lifespan. Our research has shown that the study of GAPs could be a promising new avenue of research for ageing researchers. Further analysis of CG42795 could lead to the development of potential autophagy activators.
Longevity Relevance Analysis
(4)
Silencing the GTPase-activating protein CG42795 enhances autophagy and prolongs lifespan in Drosophila. The paper addresses mechanisms that could potentially stimulate autophagy, which is directly related to the aging process and longevity research.
Yosra Bejaoui, Luma Srour, Abeer Qannan ...
· GeroScience
· College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar.
· pubmed
Several progeroid syndromes' causative mutations have been linked to epigenetic age acceleration as measured via several epigenetic clocks. At the same time, several protective variants have also been discovered that can reduce the risk of developing certain age-related disorders...
Several progeroid syndromes' causative mutations have been linked to epigenetic age acceleration as measured via several epigenetic clocks. At the same time, several protective variants have also been discovered that can reduce the risk of developing certain age-related disorders. However, the impact of these protective variants on epigenetic aging has not been well elucidated. Our research, which involved screening over 14,669 healthy individuals enrolled in the Qatar BioBank (QBB) and sequenced by the Qatar Genome Project (QGP), identified individuals carrying protective variants against age-related disorders, including Alzheimer's disease (AD), type 2 diabetes (T2D), and atherosclerosis. In this study, we measured methylation levels in blood DNA using the EPIC v2 arrays. In addition, epigenetic age was calculated using various epigenetic clocks. Our analysis revealed that the APOE*E2 protective variant reduces the rate of GrimAge epigenetic aging when compared to individuals with the APOE4 AD risk allele. Furthermore, our differential DNA methylation analysis discovered the association of the PCSK9 protective variant with specific biological processes related to immune function and the cardiovascular system. In conclusion, APOE*E2 protective variants have a positive impact on epigenetic aging, while PCSK9 protective variants have a significant effect on DNA methylation signatures. Further studies are needed to better understand the underlying mechanisms by which protective variants influence epigenetic aging, particularly the role of APOE*E2 protective variants in biological aging. Furthermore, additional research is required to fully uncover the processes that might enable specific targeted therapies to mimic the effects of beneficial mutations, such as LOF variants in PCSK9, in reducing the risk of geriatric disorders.
Longevity Relevance Analysis
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The paper claims that protective genetic variants, specifically APOE*E2, can reduce the rate of epigenetic aging. This research is relevant as it explores the genetic factors that may influence the biological mechanisms of aging, potentially leading to insights on longevity and age-related diseases.