Chia-Ling Kuo, Peiran Liu, Gabin Drouard ...
· Proteomics
· Department of Public Health Sciences, University of Connecticut Health Center, Farmington, CT 06032.
· pubmed
The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-ba...
The focus of aging research has shifted from increasing lifespan to enhancing healthspan to reduce the time spent living with disability. Despite significant efforts to develop biomarkers of aging, few studies have focused on biomarkers of healthspan. We developed a proteomics-based signature of healthspan [healthspan proteomic score (HPS)] using proteomic data from the Olink Explore 3072 assay in the UK Biobank Pharma Proteomics Project (53,018 individuals and 2,920 proteins). A lower HPS was associated with higher mortality risk and several age-related conditions, such as chronic obstructive pulmonary disease, diabetes, heart failure, cancer, myocardial infarction, dementia, and stroke. HPS showed superior predictive accuracy for these outcomes compared to other biological age measures. Proteins associated with HPS were enriched in hallmark pathways such as immune response, inflammation, cellular signaling, and metabolic regulation. The external validity was evaluated using the Essential Hypertension Epigenetics study with proteomic data also from the Olink Explore 3072 and complementary epigenetic data, making it a valuable tool for assessing healthspan and as a potential surrogate marker to complement existing proteomic and epigenetic biological age measures in geroscience-guided studies.
Longevity Relevance Analysis
(5)
The paper claims that a proteomic signature (healthspan proteomic score) can predict mortality risk and age-related conditions more accurately than existing biological age measures. This research is relevant as it focuses on identifying biomarkers that could enhance healthspan, addressing the root causes of aging rather than merely treating age-related diseases.
de Lima Camillo, L. P., Gam, R., Maskalenka, K. ...
· cell biology
· Shift Bioscience Ltd
· biorxiv
Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: \"OSK(M)\") have been...
Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: \"OSK(M)\") have been shown to rejuvenate cells based on accurate predictors of age known as epigenetic clocks. Unfortunately, OSK(M) induces dangerous pluripotency pathways, making it unsuitable for therapeutic use. Recent work has focused on minimising the danger of the cocktail, but safety concerns remain. Here we present \"SB000\", the first single gene intervention to rejuvenate cells from multiple germ layers with efficacy rivalling the Yamanaka factors. Cells rejuvenated by SB000 retain their somatic identity, without evidence of pluripotency or loss of function. These results reveal that decoupling pluripotency from cell rejuvenation does not remove the ability to rejuvenate multiple cell types. This discovery paves the way for cell rejuvenation therapeutics that can be broadly applied across age-driven diseases.
Longevity Relevance Analysis
(5)
The paper claims that the single gene intervention "SB000" can rejuvenate cells from multiple germ layers without inducing pluripotency. This research is relevant as it addresses the root causes of aging by proposing a novel approach to cellular rejuvenation, potentially leading to therapies that combat age-related diseases.
Sadoughi, B., Hernandez-Rojas, R., Hamou, H. ...
· genomics
· Arizona State University
· biorxiv
Elucidating the socio-ecological factors that shape patterns of epigenetic modification in long-lived vertebrates is of broad interest to evolutionary biologists, geroscientists, and ecologists. However, aging research in wild populations is limited due to inability to measure ce...
Elucidating the socio-ecological factors that shape patterns of epigenetic modification in long-lived vertebrates is of broad interest to evolutionary biologists, geroscientists, and ecologists. However, aging research in wild populations is limited due to inability to measure cellular hallmarks of aging noninvasively. Here, we demonstrate that cellular DNA methylation (DNAm) profiles from fecal samples provide an accurate and reliable molecular clock in wild capuchin monkeys. Analysis of blood, feces, and urine samples from a closely related species shows that DNAm differentiates between species and different types of biological samples. We further find age-associated differences in DNAm relevant to cellular damage, inflammation, and senescence, consistent with hallmarks conserved across humans and other mammalian species, speaking to the comparative potential. By demonstrating that DNAm can be studied non-invasively in wild animals, our research opens new avenues in the study of modifiers of the pace of aging, and increases potential for cross-population and species comparisons.
Longevity Relevance Analysis
(5)
The paper claims that non-invasive DNA methylation profiles from fecal samples can serve as a reliable molecular clock for aging in wild capuchin monkeys. This research is relevant as it explores the molecular mechanisms of aging and provides a novel method for studying aging in natural populations, which could lead to insights into the root causes of aging and its modifiers.
Shemtov, S. J., McGann, E., Carrillo, L. ...
· molecular biology
· University of Southern California
· biorxiv
Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most ...
Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian lifespan and protects against a range of age-related diseases. Surprisingly though, we found that reduced IGF-1 signaling fails to extend the lifespan of mitochondrial mutator mice. Accordingly, most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the pro-longevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome and that mitochondrial mutations may impose a hard limit on mammalian lifespan. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.
Longevity Relevance Analysis
(5)
Reduced IGF-1 signaling's pro-longevity effects are contingent on mitochondrial genome stability. This paper is relevant as it explores the mechanisms underlying lifespan extension and the critical role of mitochondrial integrity in aging.
Soe Maung Maung Phone Myint, Alexander Tate Lasher, Kaimao Liu ...
· Aging cell
· Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
· pubmed
Multiple studies in mice with genetically disrupted growth hormone (GH) signaling have demonstrated that such disruption results in reduced body size, robustly increased longevity (> 50% in some cases), and improvements across multiple health parameters. However, it remains uncle...
Multiple studies in mice with genetically disrupted growth hormone (GH) signaling have demonstrated that such disruption results in reduced body size, robustly increased longevity (> 50% in some cases), and improvements across multiple health parameters. However, it remains unclear how generalizable these findings are across mammals. Evidence in rats is limited and inconsistent. These conflicting results highlight the need for further investigation into the role of GH signaling in longevity across species. To address this gap, we developed a novel GH-deficient rat model using CRISPR/Cas9 technology to introduce a 10 bp deletion in exon 3 of the gene encoding rat GH-releasing hormone (GHRH) yielding a non-functional GHRH product. Physiological characterization of GHRH knockout (KO) rats revealed that they were half the body weight of wild-type controls. Additionally, relative to controls, they displayed an increased percent body fat, enhanced insulin sensitivity, reduced circulating insulin-like growth factor I (IGF-I) concentration, and a decreased reliance on glucose oxidation for energy metabolism, as determined by indirect calorimetry. Analysis of the gut microbial community in adult GHRH-KO rats further revealed a less diverse male microbiome, but a more diverse female KO microbiome compared to controls. Collectively, these findings demonstrate that multiple aspects of the GH activity-deficient phenotype, well-documented in mice, are faithfully recapitulated in our rat model. Therefore, the GHRH-deficient rat model represents a valuable new tool for advancing our understanding of the role of GH signaling in aging processes.
Longevity Relevance Analysis
(4)
The paper claims that a novel GH-deficient rat model recapitulates key aspects of growth hormone signaling's role in aging. This research is relevant as it explores the underlying mechanisms of aging through genetic manipulation, potentially offering insights into longevity across species.
Sturmlechner, I., Jain, A., Jiang, J. ...
· immunology
· Mayo Clinic
· biorxiv
Older adults are susceptible to infections, in part due to waning of immune memory. To determine mechanisms that determine long-lasting versus short-term immunity, we examined varicella zoster virus (VZV) vaccination as a model system. We contrasted VZV antigen-specific T cells s...
Older adults are susceptible to infections, in part due to waning of immune memory. To determine mechanisms that determine long-lasting versus short-term immunity, we examined varicella zoster virus (VZV) vaccination as a model system. We contrasted VZV antigen-specific T cells several years after vaccination in adults who had been vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine that confers durable protection only when given at young age, or with an adjuvanted VZV component vaccine that elicits effective, long-lasting immunity in older adults. CD8+ T cells were highly sensitive to age-related changes showing T cell subset shifts, loss in TCR diversity and reduced stem-like features while gaining NK-like signatures without evidence for cellular senescence or exhaustion. VZV-specific CD4+ T cells were largely resilient to age and maintained phenotypic and TCR diversity. Immunization of older adults with the adjuvanted VZV vaccine did not reverse age-associated defects in CD8+ T cells. Instead, it selectively improved the functionality of VZV-specific Th17 CD4+ T cells and prevented their acquisition of Treg features, likely as consequence of lipid metabolic pathways. Collectively, our data indicate that effective vaccination in older adults is supported by the generation of a durable, antigen-specific CD4+ Th17 population that resists mis-differentiation into Tregs and that compensates for age-related defects in CD8+ T cells.
Longevity Relevance Analysis
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The paper claims that antigen-specific Th17 CD4+ T cells can improve immune responses in older adults by offsetting age-related defects in CD8+ T cells. This research is relevant as it explores mechanisms to enhance immune memory and functionality in aging, addressing a root cause of susceptibility to infections in older populations.
Ming Ann Sim, Jorming Goh, Jasinda Lee ...
· Sirolimus
· Centre for Healthy Longevity, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. [email protected].
· pubmed
The geroprotective effects of rapamycin in mitigating frailty and cognitive complications in the perioperative period remains unknown. Of 39 C57BL/6 mice tested, 19 were young (16 weeks), and 20 were old (80 weeks). The interventional group (10 old, 10 young) received daily oral ...
The geroprotective effects of rapamycin in mitigating frailty and cognitive complications in the perioperative period remains unknown. Of 39 C57BL/6 mice tested, 19 were young (16 weeks), and 20 were old (80 weeks). The interventional group (10 old, 10 young) received daily oral rapamycin for 8 weeks pre-op compared to controls (10 old, 9 young). Sham laparotomy was performed at week 9. Perioperative frailty was assessed using a murine clinical frailty scale, preoperatively and at 1, 4 and 8 weeks postoperatively. Spatial memory was assessed using the Barnes maze preoperatively, and at weeks 1 and 4 post-op. Rapamycin treatment is associated with significantly less decline in postoperative clinical frailty(p < 0.05). Subgroup analysis revealed similar findings for old and young mice. The rapamycin group demonstrated improved cognitive performance at 1-week postoperatively (β 40.18, 95%C.I. 8.70-71.67, p = 0.012), but only in older mice (β 54.51, 95%C.I. 6.77-102.25, p = 0.025). In a pre-clinical animal model of anesthesia and surgery, rapamycin supplementation protected against surgery-induced frailty and short-term postoperative cognitive dysfunction.
Longevity Relevance Analysis
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Rapamycin supplementation mitigates perioperative frailty and cognitive decline in a murine model. The study addresses the potential geroprotective effects of rapamycin, which is directly related to understanding and potentially intervening in the aging process.
Jia Xie, Ze-Guang Han
· BioEssays : news and reviews in molecular, cellular and developmental biology
· Key Laboratory of Systems Biomedicine (Ministry of Education) and State Key Laboratory of Medical Genomics, Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.
· pubmed
Heterochromatin, a crucial constituent of the eukaryotic nucleus with highly conserved and transcriptionally silenced characteristics, plays a pivotal role in safeguarding genome stability, regulating nuclear morphology, and mediating cell fate. Recent convincing evidence indicat...
Heterochromatin, a crucial constituent of the eukaryotic nucleus with highly conserved and transcriptionally silenced characteristics, plays a pivotal role in safeguarding genome stability, regulating nuclear morphology, and mediating cell fate. Recent convincing evidence indicates that the formation and maintenance of heterochromatin are implicated in cellular senescence and age-associated disorders. Interestingly, an attractive mechanism involving liquid-liquid phase separation (LLPS) may exert a central role in regulating heterochromatin formation and maintenance. In this review, we provide an overview of recent research to illustrate the role and regulatory mechanism of the biomolecular condensates in the regulation of heterochromatin stabilization. In addition, we elucidate how heterochromatin loss contributes to cellular senescence by triggering genome instability, and explore the potential therapeutic strategies to counteract cellular senescence and age-related pathologies by restoring heterochromatin stability. Finally, we outline current research challenges and future directions aimed at achieving a more comprehensive understanding of the link among heterochromatin regulation, phase separation, and cellular senescence, for ameliorating the effects of ageing in the future.
Longevity Relevance Analysis
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The paper discusses the role of biomolecular condensates in stabilizing heterochromatin and their implications for cellular senescence and age-related pathologies. This research is relevant as it addresses mechanisms that could potentially mitigate the root causes of aging and cellular decline.
Rychlicka-Buniowska, E., Sarkisyan, D., Horbacz, M. ...
· genetic and genomic medicine
· Department of Immunology, Genetics and Pathology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden; 3P-Medicine Laboratory, Medical Universit
· medrxiv
Loss of Y chromosome (LOY) and clonal hematopoiesis of indeterminate potential (CHIP) are common age-related events associated with multiple adverse outcomes in the elderly. While LOY has been associated with higher risk of Alzheimer disease (AD), CHIP has been suggested to perfo...
Loss of Y chromosome (LOY) and clonal hematopoiesis of indeterminate potential (CHIP) are common age-related events associated with multiple adverse outcomes in the elderly. While LOY has been associated with higher risk of Alzheimer disease (AD), CHIP has been suggested to perform a protective role against AD. Moreover, the co-occurrence of CHIP and LOY is debated. We performed deep whole-exome sequencing of FACS-isolated CD4T lymphocytes, NK and myeloid cells from men with AD and controls exhibiting either LOY or retention of Y chromosome (ROY). We found 39 sequence variants in known (canonical) myeloid driver genes of clonal hematopoiesis (MD-CH) and known lymphoid driver genes (LD-CH), and maximally 14(35%) of these could co-exist with LOY within the same clone. We further describe 192 unknown drivers of clonal hematopoiesis (UD-CH), which were markedly enriched in AD-LOY individuals (odds ratio=4.8, Benjamini-Hochberg adjustedp=0.041), and over 20% of these variants were protein-truncating. In myeloid cells, the total burden of all detected drivers correlated with the percentage of LOY cells (Spearman{rho}=0.52, adjustedp=0.00041). In conclusion, our findings suggest that LOY acts as the primary driver of clonal hematopoiesis in AD by seeding myeloid clones. These clones may subsequently accumulate additional, often truncating, UD variants, while most canonical CHIP mutations arise independently of LOY. Our study delineates distinct yet partially overlapping clonal architectures for LOY and CHIP in late-onset AD and underscores LOY-driven myeloid expansion as a potential contributor to disease pathogenesis.
Longevity Relevance Analysis
(4)
The paper claims that loss of Y chromosome (LOY) drives clonal hematopoiesis in Alzheimer disease (AD) by seeding myeloid clones that may contribute to disease pathogenesis. This research is relevant as it explores the underlying mechanisms of age-related diseases, specifically how genetic factors like LOY may influence the progression of Alzheimer's, thereby addressing potential root causes of aging-related pathologies.
McQuade, A., Castillo, V. C., Hagan, V. ...
· neuroscience
· University of California, San Francisco
· biorxiv
Microglia dynamically support brain homeostasis through the induction of specialized activation programs or states. One such program is the Interferon-Responsive Microglia state (IRM), which has been identified in developmental windows, aging, and disease. While the functional im...
Microglia dynamically support brain homeostasis through the induction of specialized activation programs or states. One such program is the Interferon-Responsive Microglia state (IRM), which has been identified in developmental windows, aging, and disease. While the functional importance of this state is becoming increasingly clear, our understanding of the regulatory networks that govern IRM induction remain incomplete. To systematically identify genetic regulators of the IRM state, we conducted a genome-wide CRISPR interference (CRISPRi) screen in human iPSC-derived microglia (iPS-Microglia) using IFIT1 as a representative IRM marker. We identified 772 genes that modulate IRM, including canonical type I interferon signaling genes (IFNAR2, TYK2, STAT1/2, USP18) and novel regulators. We uncovered a non-canonical role for the CCR4-NOT complex subunit CNOT10 in IRM activation, independent of its traditional function. This work provides a comprehensive resource for dissecting IRM biology and highlights both established and novel targets for modulating microglial interferon signaling in health and disease.
Longevity Relevance Analysis
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The paper identifies genetic regulators of the Interferon-Responsive Microglia state, which is implicated in aging and disease. Understanding the regulatory networks of microglia in the context of aging could provide insights into the mechanisms of age-related neurodegeneration and potential interventions.
Palomares, D., Vanparys, A., Jorgji, J. ...
· neuroscience
· Aging and Dementia group, Cellular and Molecular Division (CEMO), Institute of Neuroscience (IoNS), UCLouvain, Brussels, Belgium
· biorxiv
Background: Although the connection between aging and neurodegenerative pathologies like Alzheimer\'s disease (AD) has long been recognized, the underlying pathological mechanisms remain largely unknown. Senescent brain cells build up in the brains of AD patients and a causal lin...
Background: Although the connection between aging and neurodegenerative pathologies like Alzheimer\'s disease (AD) has long been recognized, the underlying pathological mechanisms remain largely unknown. Senescent brain cells build up in the brains of AD patients and a causal link has been established between senescence and AD-related tauopathy. Methods: To investigate the role of cellular senescence in tau-mediated neuropathology, we crossed the Terc knockout (Terc-/-) senescent mouse model with the P301S tauopathy model (PS19 line). Using brain sections and protein extracts, we employed Western blot and immunostaining analyses to investigate the expression of tau-related neuropathological features within a senescent context. Results: We found that the brains of 6- and 9-month-old Terc-/- mice exhibit significant telomere attrition and signs of cellular senescence. Introducing a senescent phenotype in a tauopathy mouse model resulted in increased tau phosphorylation at key residues, particularly in the hippocampus. Over time, this was associated with enhanced tau truncation and aggregation. These pathological changes were accompanied by exacerbated astrocyte and microglial activation, as well as selective neuronal loss in vulnerable brain regions. Conclusions: Overall, our findings place senescence as a key upstream regulator of tau pathology, suggesting that targeting senescent cells and their detrimental effects may offer promising therapeutic strategies for AD and other related tauopathies.
Longevity Relevance Analysis
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The paper claims that cellular senescence is a key upstream regulator of tau pathology in neurodegeneration. This research is relevant as it explores the underlying mechanisms of aging-related neurodegenerative diseases and suggests potential therapeutic strategies targeting senescent cells, addressing root causes of aging rather than merely treating symptoms.
Hiroshi Kobayashi, Shogo Imanaka
· DNA, Mitochondrial
· Department of Gynecology and Reproductive Medicine, Ms.Clinic MayOne, Kashihara, Nara 634‑0813, Japan.
· pubmed
Mitochondria and mitochondrial DNA (mtDNA) are crucial for cellular energy metabolism and the adaptive response to environmental changes. mtDNA collaborates with the nuclear genome to regulate mitochondrial function. Dysfunctional mitochondria and mutations in mtDNA are implicate...
Mitochondria and mitochondrial DNA (mtDNA) are crucial for cellular energy metabolism and the adaptive response to environmental changes. mtDNA collaborates with the nuclear genome to regulate mitochondrial function. Dysfunctional mitochondria and mutations in mtDNA are implicated in a wide range of diseases, including mitochondrial disorders, neurodegenerative conditions, age‑associated pathologies and cancer. While the nuclear genome has been extensively studied for its role in driving the clonal expansion of oncogenes and other aging‑related genetic alterations, knowledge regarding mtDNA remains comparatively limited. However, advances in quantitative analysis have provided information regarding the complex patterns of mtDNA mutations. The present review offers a detailed examination of mtDNA mutations and their classifications in the contexts of aging and cancer, and elucidates the role of mtDNA mutations in these processes. Mutations in mtDNA can be detected as early as the neonatal stage, yet most transition mutations retain a normal cellular phenotype. In contrast to mutations in oncogenes and tumor suppressor genes within the nuclear genome, mtDNA exhibits conserved mutational signatures, irrespective of cancer tissue origin. To adapt to the aging process, mitochondria undergo clonal expansion of advantageous mtDNA mutations, maintaining a dynamic equilibrium among various mitochondrial clones. Over time, however, the loss of strand bias can disrupt this equilibrium, diminishing the pool of adaptive clones. This breakdown in mitochondrial homeostasis may contribute to tumorigenesis. In conclusion, the heterogeneity of mtDNA mutations and the collapse of its homeostasis are pivotal in the progression of age‑related diseases, including cancer, underscoring the importance of mtDNA mutations in health and disease.
Longevity Relevance Analysis
(4)
Mitochondrial DNA mutations play a significant role in the aging process and cancer development. The paper discusses the implications of mtDNA mutations in age-related diseases, addressing underlying mechanisms that contribute to aging rather than merely treating symptoms.
Matías Fuentealba, Laure Rouch, Sophie Guyonnet ...
· Nature aging
· Buck AI Platform, Buck Institute for Research on Aging, Novato, CA, USA.
· pubmed
Age-related decline in intrinsic capacity (IC), defined as the sum of an individual's physical and mental capacities, is a cornerstone for promoting healthy aging by prioritizing maintenance of function over disease treatment. However, assessing IC is resource-intensive, and the ...
Age-related decline in intrinsic capacity (IC), defined as the sum of an individual's physical and mental capacities, is a cornerstone for promoting healthy aging by prioritizing maintenance of function over disease treatment. However, assessing IC is resource-intensive, and the molecular and cellular bases of its decline are poorly understood. Here we used the INSPIRE-T cohort (1,014 individuals aged 20-102 years) to construct the IC clock, a DNA methylation-based predictor of IC, trained on the clinical evaluation of cognition, locomotion, psychological well-being, sensory abilities and vitality. In the Framingham Heart Study, DNA methylation IC outperforms first-generation and second-generation epigenetic clocks in predicting all-cause mortality, and it is strongly associated with changes in molecular and cellular immune and inflammatory biomarkers, functional and clinical endpoints, health risk factors and lifestyle choices. These findings establish the IC clock as a validated tool bridging molecular readouts of aging and clinical assessments of IC.
Longevity Relevance Analysis
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The paper claims that a blood-based epigenetic clock can predict intrinsic capacity and mortality, linking molecular aging markers to clinical assessments. This research is relevant as it addresses the underlying mechanisms of aging and intrinsic capacity, which are crucial for promoting healthy aging and understanding the biological basis of longevity.
Mareike Peters, Patric Teodorescu, Sergiu Pasca ...
· Haematologica
· Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.
· pubmed
Not available.
Not available.
Longevity Relevance Analysis
(4)
The paper claims to comprehensively characterize age-related changes in the human bone marrow microenvironment. This research is relevant as it addresses the biological changes associated with aging, which could provide insights into the underlying mechanisms of aging and potential interventions.
Xiao-Wei Liu, Hao-Wei Xu, Shu-Bao Zhang ...
· Cell death discovery
· Department of Spinal Surgery, Shanghai East Hospital, School of Medicine, Tongji University, 200092, Shanghai, China.
· pubmed
Intervertebral disc degeneration (IVDD) is a common pathology involving various degenerative diseases of the spine, with nucleus pulposus cell (NPC) senescence playing an important role in its pathogenesis. Transcriptional and epigenetic processes have been increasingly implicate...
Intervertebral disc degeneration (IVDD) is a common pathology involving various degenerative diseases of the spine, with nucleus pulposus cell (NPC) senescence playing an important role in its pathogenesis. Transcriptional and epigenetic processes have been increasingly implicated in aging and longevity. E74-like factor 1 (ELF1) is a member of the erythroblast transformation specific family of proteins, which induce gene transcription by binding to gene promoters or enhancer sequences. However, the role of ELF1 in age-related diseases is unclear, with no reports of its involvement in NPC senescence or IVDD. ELF1 expression levels were assessed in human NP samples from IVDD patients, IVDD animal models, and naturally aged NP samples. Adeno-associated virus 5 (AAV5) vector-mediated Elf1 overexpressing mice and Elf1 knockout (KO) mice were used to investigate its role in NPC senescence and IVDD in vivo. The m6A methylase METTL3 and reading protein YTHDF2 were identified as downstream effectors of ELF1 using proteomic sequencing, RNA sequencing, ChIP-seq, promoter prediction, and binding analyses. MepRIP-qPCR, RNA pulldown, and double luciferase point mutation experiments revealed that METTL3 and YTHDF2 can recognize the m6A site on E2F3 mRNA, a key cell cycle gene. Finally, virtual screening techniques and various experiments were used to identify small molecule targets for ELF1 inhibition. ELF1 was found to drive m6A modification changes during NPC aging. The small molecule mycophenolate mofetil (MMF) could successfully target and inhibit ELF1 expression. In senescent NPCs, ELF1 can bind to the METTL3 and YTHDF2 gene promoter regions. Overexpressing METTL3 increased the E2F3 mRNA m6A modification abundance, while YTHDF2 was recruited to recognize this m6A site. This can accelerate the E2F3 mRNA degradation rate and ultimately lead to the onset of G1/S cell cycle arrest in NPC. For the first time, the transcription factor ELF1 has been identified as a novel regulator of NPC senescence and IVDD, which involves the ELF1-METTL3/YTHDF2-m6A-E2F3 axis. MMF, a small molecule designed to inhibit ELF1 and delay NPC senescence, was screened for the first time. This can potentially lead to new epigenetic therapeutic strategies for drug discovery and development for the clinical treatment of IVDD.
Longevity Relevance Analysis
(4)
The paper identifies ELF1 as a novel regulator of nucleus pulposus cell senescence and intervertebral disc degeneration through the ELF1-METTL3/YTHDF2-m6A-E2F3 axis. This research is relevant as it explores the underlying mechanisms of cellular senescence, which is a key factor in aging and age-related diseases, potentially leading to therapeutic strategies that address the root causes of aging.
Rooban Sivakumar, K A Arul Senghor, V M Vinodhini ...
· Drugs & aging
· Department of Biochemistry, SRM Medical College Hospital and Research Centre, SRM Institute of Science and Technology, SRM Nagar, Kattankulathur, Kanchipuram, Chennai, Tamil Nadu, 603203, India. [email protected].
· pubmed
Metformin, traditionally promoted for its efficacy in diabetes, is increasingly appreciated for its geroprotective potential in the development of vascular aging, a key contributor to cardiovascular morbidity. This review aims at understanding the spectrum of mechanisms that gove...
Metformin, traditionally promoted for its efficacy in diabetes, is increasingly appreciated for its geroprotective potential in the development of vascular aging, a key contributor to cardiovascular morbidity. This review aims at understanding the spectrum of mechanisms that govern the amelioration of degenerative processes associated with vascular aging by metformin. Central to this therapeutic promise is the activation of AMPK, which reduces metabolic dysregulation and hence slows vascular senescence. Oxidative stress has been identified as an important mechanism thought to be enhanced by metformin in the preservation of endothelial function and attenuation of arterial stiffening. Besides, metformin has lipid-lowering and antiinflammatory activity, which is critical for reducing arterial rigidity and the development of atherosclerotic plaque. In recent times, both clinical and preclinical studies revealed empirical data that confirmed the effectiveness of metformin in the improvement of endothelial function and the decreasing of arterial stiffness as a part of a reduction in the rates of cardiovascular events. The therapeutic action of the drug goes beyond glycemic control, rendering it a geroprotector potentially suitable for broader application in age-related vascular decline. In light of these findings, the clinical acceptance of metformin as an intervention in vascular aging should be possible and promising. Carefully monitored follow-up studies are needed to optimize dosing, delineate the broad biological effects, and verify long-term benefits, which will underpin metformin's role in the paradigm against age-associated vascular diseases.
Longevity Relevance Analysis
(4)
Metformin may serve as a geroprotector by ameliorating vascular aging through mechanisms such as AMPK activation and reduction of oxidative stress. The paper addresses the potential of metformin to target underlying mechanisms of aging rather than merely treating age-related symptoms, aligning with longevity research goals.
Jackson Nuss, Matt Kaeberlein, Alessandro Bitto ...
· GeroScience
· Department of Laboratory Medicine & Pathology, School of Medicine, University of Washington, Seattle, WA, USA.
· pubmed
Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the p...
Mice missing the complex I subunit Ndufs4 of the electron transport chain are widely used as a leading animal model of Leigh syndrome, a pediatric neurodegenerative disorder that leads to premature death. More broadly, this animal model has enabled a better understanding of the pathophysiology of mitochondrial disease and mitochondrial dysfunction in sporadic disorders. Intriguingly, longevity interventions are very effective at treating symptoms of disease in this model. Herein, we introduce the model and its notable features that may help provide insights in longevity research. We performed a retrospective analysis of historical data from our laboratories over the past 10 years regarding the use of this animal model in aging studies, the manifestation and progression of mitochondrial disease, and factors that influence their premature death. We observed a correlation between weight and lifespan in female animals and a sex-independent correlation between the onset of clasping, a typical neurodegenerative symptom, and overall survival. We observed a sexual dimorphism in lifespan with female mice being more resilient despite a similar age of onset of disease symptoms. Lastly, we report increased lifespan and delayed onset of disease symptoms following treatment with 17-alpha-estradiol, a non-feminizing estrogen which can extend lifespan in genetically heterogeneous mice. This analysis serves as a useful guide for researchers utilizing this animal in the discovery of effective interventions for longevity and to prevent the onset of disease. It suggests there may be unprecedented underlying sex-specific differences in patients with Leigh syndrome and further strengthens the connection between normative aging and mitochondrial dysfunction.
Longevity Relevance Analysis
(4)
The paper claims that treatment with 17-alpha-estradiol can increase lifespan and delay disease onset in a mouse model of Leigh syndrome. This research is relevant as it explores potential interventions that may address underlying mechanisms of aging and mitochondrial dysfunction, contributing to the understanding of longevity.
Jing, Y., Li, L., Guo, W. ...
· cell biology
· Department of Urology, Shanghai General 32 Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 33 200080, China
· biorxiv
Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to...
Benign prostatic hyperplasia (BPH) is a common age-associated urological condition characterized by stromal expansion, but its cellular origins and regulatory mechanisms remain unclear. In this study, we identified endothelial-to-mesenchymal transition (EndMT) as a contributor to stromal cell accumulation in BPH. Using single-cell transcriptomic analysis, endothelial lineage tracing in mice, and validation in human samples, we showed that senescence-associated mast cells increased the expression of vascular endothelial growth factor A (VEGFA) and transforming growth factor-beta 1 (TGF-{beta}1) through the stem cell factor (SCF)/c-KIT-MAPK-JUND signaling pathway, thereby inducing EndMT in endothelial progenitor cells. Stromal fibroblasts express SCF, promoting mast cell activation and establishing a feedback loop that supports continued stromal proliferation. Intriguingly, inhibition of mast cell activation reduces EndMT and attenuates prostate enlargement in vivo.Thus, these findings revealed a senescence-linked immune - stromal interaction in the aging prostate and identify potential targets for therapeutic intervention in BPH.
Longevity Relevance Analysis
(4)
Senescent mast cells promote endothelial-to-mesenchymal transition in benign prostatic hyperplasia through the SCF/c-KIT signaling pathway. This study addresses the role of cellular senescence in a specific age-related condition, linking immune responses to stromal changes, which could inform therapeutic strategies targeting aging mechanisms.
Salignon, J., Tsiokou, M., Marques, P. ...
· bioinformatics
· Karolinska Institute
· biorxiv
As the prevalence of age-related diseases rises, understanding and modulating the aging process is becoming a priority. Transcriptomic aging clocks (TACs) hold great promise for this endeavor, yet most are hampered by platform or tissue specificity and limited accessibility. Here...
As the prevalence of age-related diseases rises, understanding and modulating the aging process is becoming a priority. Transcriptomic aging clocks (TACs) hold great promise for this endeavor, yet most are hampered by platform or tissue specificity and limited accessibility. Here, we introduce Pasta, a robust and broadly applicable TAC based on a novel age-shift learning strategy. Pasta accurately predicts relative age from bulk, single-cell, and microarray data, capturing senescent and stem-like cellular states through signatures enriched in p53 and DNA damage response pathways. Its predictions correlate with tumor grade and patient survival, underscoring clinical relevance. Applied to the CMAP L1000 dataset, Pasta identified known and novel age-modulatory compounds and genetic perturbations, and highlighted mitochondrial translation and mRNA splicing as key determinants of the cellular propensity for aging and rejuvenation, respectively. Supporting Pasta\'s predictive power, we validated pralatrexate as a potent senescence inducer and piperlongumine as a rejuvenating agent. Strikingly, chemotherapy drugs were highly enriched among pro-aging hits. Taken together, Pasta represents a powerful and generalizable tool for aging research and therapeutic discovery, distributed as an easy-to-use R package on GitHub.
Longevity Relevance Analysis
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Pasta is a transcriptomic aging clock that identifies chemical and genetic determinants of aging and rejuvenation. The paper is relevant as it addresses the underlying mechanisms of aging and proposes a tool for therapeutic discovery aimed at modulating the aging process.
Bradley Olinger, Reema Banarjee, Amit Dey ...
· Nature aging
· Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.
· pubmed
Cellular senescence increases with age and contributes to age-related declines and pathologies. We identified circulating biomarkers of senescence and related them to clinical traits in humans to facilitate future noninvasive assessment of individual senescence burden, and effica...
Cellular senescence increases with age and contributes to age-related declines and pathologies. We identified circulating biomarkers of senescence and related them to clinical traits in humans to facilitate future noninvasive assessment of individual senescence burden, and efficacy testing of novel senotherapeutics. Using a nanoparticle-based proteomic workflow, we profiled the senescence-associated secretory phenotype (SASP) in THP-1 monocytes and examined these proteins in 1,060 plasma samples from the Baltimore Longitudinal Study of Aging. Machine-learning models trained on THP-1 monocyte SASP associated SASP signatures with several age-related phenotypes in a test cohort, including body fat composition, blood lipids, inflammatory markers and mobility-related traits, among others. Notably, a subset of SASP-based predictions, including a high-impact SASP panel, were validated in InCHIANTI, an independent aging cohort. These results demonstrate the clinical relevance of the circulating SASP and identify potential senescence biomarkers that could inform future clinical studies.
Longevity Relevance Analysis
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The paper claims that circulating biomarkers of the senescence-associated secretory phenotype (SASP) can predict age-related clinical outcomes in humans. This research is relevant as it addresses cellular senescence, a fundamental mechanism of aging, and seeks to identify biomarkers that could lead to noninvasive assessments of senescence burden, potentially informing interventions that target the root causes of aging.
Keyu Kong, Li Liu, Renfang Zhang ...
· Lopinavir
· Shanghai Key Laboratory of Orthopaedic Implants, Department of Orthopaedic Surgery, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
· pubmed
Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome (AIDS) patients has remained contentious, with conjectures pointing towards its correlation with distinct antiviral regimes. Protease inhibitors (PIs) stand as a prominent class of antivira...
Debate regarding the premature aging of knee joints in acquired immune deficiency syndrome (AIDS) patients has remained contentious, with conjectures pointing towards its correlation with distinct antiviral regimes. Protease inhibitors (PIs) stand as a prominent class of antiviral agents frequently utilized in AIDS management and have been significantly linked to premature senescence. This study aimed to investigate whether PI-containing regimens would accelerate osteoarthritis (OA) development and explore the molecular mechanisms underlying this association. A retrospective cohort of 151 HIV-infected individuals, categorized into PI and non-PI groups, was established. Patients in PI group exhibited lower KOOS and a higher prevalence of radiological knee OA than those in non-PI group. Additionally, 25 anti-HIV drugs were screened and among all antiviral drugs, lopinavir had the most detrimental impact on cartilage anabolism, accelerating cartilage senescence and promoting mouse OA development. Mechanistically, lopinavir accelerated cellular senescence by inhibiting Zmpste24 and interfering nuclear membrane stability, which leads to decreased binding between nuclear membrane-binding protein Usp7 and Mdm2 and activates Usp7/Mdm2/p53 pathway. Zmpste24 overexpression reduces OA severity in mice. These findings suggest that PI-containing regimens accelerate cartilage senescence and OA development through Zmpste24 inhibition, which provides new insights into the selection of HIV regimens.
Longevity Relevance Analysis
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The study claims that lopinavir, a protease inhibitor used in AIDS treatment, accelerates knee osteoarthritis progression through Zmpste24 inhibition. This research is relevant as it explores the molecular mechanisms linking antiviral treatment to accelerated aging processes in joint health, contributing to the understanding of age-related diseases.
Julian M Carosi, Alexis Martin, Leanne K Hein ...
· Autophagy
· Lysosomal Health in Ageing, Lifelong Health Theme, South Australian Health and Medical Research Institute (SAHMRI), Adelaide, South Australia, Australia.
· pubmed
Autophagy is a 'waste-disposal' pathway that protects against age-related pathology. It is widely accepted that autophagy declines with age, yet the role that sex and diet-related obesity play during aging remain unknown. Here, we present the most comprehensive in vivo study of a...
Autophagy is a 'waste-disposal' pathway that protects against age-related pathology. It is widely accepted that autophagy declines with age, yet the role that sex and diet-related obesity play during aging remain unknown. Here, we present the most comprehensive in vivo study of autophagic flux to date. We employed transgenic mice overexpressing tandem-florescent LC3B (RFP-GFP-LC3B) to measure autophagic flux in the blood (PBMCs), heart, and motor cortex neurons of aging mice that were fed regular chow or a high-fat diet for 6-, 12- or 18-months. In male mice, aging decreased autophagic flux in the heart, increased it in the blood, and had no effect in motor cortex neurons. Age-dependent changes autophagic flux were less pronounced in female mice. High-fat diet influenced autophagic flux in the blood and heart of male but not female mice. Overall, we uncovered sexual dimorphisms that underpin how autophagy changes with age across different tissues and in response to a high-fat diet.
Longevity Relevance Analysis
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The paper claims that sexual dimorphisms influence autophagic flux changes with age across different tissues in mice. This research is relevant as it investigates the mechanisms of autophagy, a critical process linked to aging and age-related diseases, and explores how factors like sex and diet may affect this process, potentially contributing to our understanding of longevity.
Oliver Polzer, E Kinloch, P J Lucassen ...
· Aging cell
· Brain Plasticity Group, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
· pubmed
Hippocampal adult neural stem cells (NSCs) contribute to neurogenesis and astrogliogenesis throughout life. They play multifaceted roles in hippocampal function, including memory processing, stress regulation, and cognitive flexibility. Located in unique neurogenic niches like th...
Hippocampal adult neural stem cells (NSCs) contribute to neurogenesis and astrogliogenesis throughout life. They play multifaceted roles in hippocampal function, including memory processing, stress regulation, and cognitive flexibility. Located in unique neurogenic niches like the subgranular zone of the hippocampal dentate gyrus, NSCs exhibit notable heterogeneity and can be classified into quiescent, activated, and intermediate transitioning states. This diversity, while instrumental to their adaptability and function, presents challenges in molecular classification and functional interrogation. Here, we discuss current limitations and compare NSC transcriptional profiles from publicly available single-cell RNA sequencing datasets. We address discrepancies in NSC classification between studies, identify conserved gene expression profiles, and propose new markers that could serve as standardized references. Furthermore, we explore how pseudotime inference analyses provide insights into the temporal dynamics of NSCs and their progression toward neural progenitors, further aiming to optimize their classification. We also examine cellular changes in NSCs during aging and explore the potential of these cells to undergo senescence. Our work helps to resolve inconsistencies in current cell-type annotations in literature and proposes a framework to study and classify the different states of NSCs, thereby offering a better understanding of their dynamic roles in neurogenesis, aging, and cellular senescence.
Longevity Relevance Analysis
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The paper identifies conserved neurogenic gene signatures and proposes new markers for classifying neural stem cells, particularly in the context of aging. This research is relevant as it addresses the cellular mechanisms of aging in neural stem cells, which could contribute to understanding and potentially mitigating age-related cognitive decline.
Aileen H Lee, Lucie Orliaguet, Yun-Hee Youm ...
· Nature metabolism
· Department of Pathology, Yale School of Medicine, New Haven, CT, USA.
· pubmed
Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermo...
Caloric restriction and methionine restriction-driven enhanced lifespan and healthspan induces 'browning' of white adipose tissue, a metabolic response that increases heat production to defend core body temperature. However, how specific dietary amino acids control adipose thermogenesis is unknown. Here, we identified that weight loss induced by caloric restriction in humans reduces thiol-containing sulfur amino acid cysteine in white adipose tissue. Systemic cysteine depletion in mice causes lethal weight loss with increased fat utilization and browning of adipocytes that is rescued upon restoration of cysteine in diet. Mechanistically, cysteine-restriction-induced adipose browning and weight loss requires sympathetic nervous system-derived noradrenaline signalling via β3-adrenergic-receptors that is independent of FGF21 and UCP1. In obese mice, cysteine deprivation induced rapid adipose browning, increased energy expenditure leading to 30% weight loss and reversed metabolic inflammation. These findings establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.
Longevity Relevance Analysis
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Cysteine depletion induces adipose tissue browning and weight loss through sympathetic nervous system signaling. This research explores metabolic mechanisms that could influence aging and longevity by addressing the role of specific amino acids in energy expenditure and fat metabolism.
Shuzo Matsubara, Kanae Matsuda-Ito, Haruka Sekiryu ...
· The EMBO journal
· Stem Cell Biology and Medicine, Department of Stem Cell Biology and Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
· pubmed
Neural stem cells (NSCs) in the mammalian brain decline rapidly with age, leading to impairment of hippocampal memory function in later life. However, the relationship between epigenetic remodeling and transcriptional regulation that compromises hippocampal NSC activity during th...
Neural stem cells (NSCs) in the mammalian brain decline rapidly with age, leading to impairment of hippocampal memory function in later life. However, the relationship between epigenetic remodeling and transcriptional regulation that compromises hippocampal NSC activity during the early stage of chronological aging remains unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq) on NSCs and newly generated neurons across different stages. Integrated data analysis revealed continuous alterations in the chromatin profile of hippocampal NSCs and their progeny from neonatal to mature adult stages, accompanied by consistent changes in transcriptional profiles. Further, decreased expression of Setd8, encoding the enzyme for histone H4 monomethylation at lysine 20 (H4K20me1), underlies age-related changes in mouse hippocampal NSCs. Notably, depletion of Setd8 elicits alterations in gene expression and epigenetic regulation that phenocopy age-related changes, and impairs NSC activity, leading to hippocampal memory deficits. Together, our study provides a global map of longitudinal chromatin and transcriptome changes during brain aging and identifies mechanistic insights into early-onset decline of NSC activity and hippocampal neurogenesis that precedes functional aging.
Longevity Relevance Analysis
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The paper claims that downregulation of Setd8 leads to age-related changes in neural stem cell activity and hippocampal memory deficits. This research is relevant as it explores the epigenetic mechanisms underlying the decline of neural stem cells with age, which is a fundamental aspect of the aging process and could inform strategies for longevity and cognitive health.
Xu Jiang, Jing Ke, Yiting Liu ...
· Biogerontology
· Department of Otorhinolaryngology-Head and Neck Surgery, Chongqing General Hospital, Chongqing University, No .118, Xingguang Avenue, Liangjiang New Area, Chongqing, 401147, China.
· pubmed
Age-related hearing loss (ARHL) is one of the most common health conditions among the elderly population. This study used machine learning to screen for a gene signature to predicts ARHL. Four ARHL mice cochlear transcriptome datasets and the mRNA sequencing of C57BL/6J mice were...
Age-related hearing loss (ARHL) is one of the most common health conditions among the elderly population. This study used machine learning to screen for a gene signature to predicts ARHL. Four ARHL mice cochlear transcriptome datasets and the mRNA sequencing of C57BL/6J mice were used for analysis. Machine learning was used to screen for gene signatures closely related to ARHL and validate them. Via qPCR, immunohistochemistry, and immunofluorescence confocal microscopy were used to assess the effect of key gene on the cochlea. The gene signature consisting of 38 genes constructed via Stepglm [forwards] had the best accuracy in the training group, with excellent accuracy and recall in the training and testing groups in predicting ARHL. The gene signature reflected active immune function. CTSS was selected as a key gene on the basis of its association with age and influence hearing loss severity. CTSS showed high expression in ARHL and enriched in the cochlear stria vascularis, which is significantly positively correlated with macrophage marker CD68 expression (R = 0.74, p = 0.006). The gene signature has good accuracy in predicting ARHL. CTSS is highly expressed in the cochleae of ARHL mice and may promote ARHL by inducing macrophage enrichment and causing low-grade inflammation.
Longevity Relevance Analysis
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The study identifies a gene signature associated with age-related hearing loss and suggests that CTSS may promote this condition through inflammation. The research is relevant as it explores genetic factors contributing to an age-related condition, potentially addressing underlying mechanisms of aging.
Tej D Azad, Marvin W Li, Chiu Ping-Yeh ...
· Spine deformity
· Department of Neurosurgery, Johns Hopkins Hospital, Baltimore, MD, USA. [email protected].
· pubmed
The incidence of spine-related pathologies is expected to increase in developed countries due to ongoing fundamental demographic shifts toward an older population. These changes present significant challenges to public health, as healthcare systems worldwide must confront the bur...
The incidence of spine-related pathologies is expected to increase in developed countries due to ongoing fundamental demographic shifts toward an older population. These changes present significant challenges to public health, as healthcare systems worldwide must confront the burden of musculoskeletal aging and its related consequences. Here, we synthesize current knowledge on the biologic mechanisms underlying musculoskeletal aging, focusing on the implications for the aging spine. The complexity of the aging process, characterized by a convoluted interplay between genetic, environmental, and lifestyle factors, necessitates a comprehensive understanding of the biologic processes and reliable methods of surveying biologic states to inform effective diagnostic, predictive, and prognostic strategies. Biomarkers emerge as invaluable tools in this domain, offering insights into the early detection, risk assessment, and targeted intervention for age-related musculoskeletal decline. This review highlights various biomarker types including diagnostic, predictive, and prognostic, and explores their distinct roles in enhancing our understanding of musculoskeletal aging. Navigating the interconnected landscape of cellular senescence, sarcopenia, osteoporosis, and frailty, this review underscores the critical importance of developing personalized care approaches for the aging population. By identifying and integrating functional biomarkers, researchers and clinicians can elucidate the underlying mechanisms and devise tailored strategies to alleviate the musculoskeletal decline associated with the aging process. We envision an "active surveillance" future where biomarkers of musculoskeletal aging are integrated into clinical practice, empowering clinicians to make proactive, data-driven decisions that improve spine health for older adults.
Longevity Relevance Analysis
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The paper claims that integrating musculoskeletal biomarkers into clinical practice can enhance the understanding and management of age-related musculoskeletal decline. This paper is relevant as it addresses the biological mechanisms of aging and proposes strategies for proactive intervention, which aligns with the goals of longevity research.
NyamErdene, A., Thao Ngoc Le, N., Nebie, O. ...
· neuroscience
· International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei ,Taiwan,Graduate Institute of Biomed
· biorxiv
Platelet-derived materials are emerging as promising, cell-free biotherapies for regenerative medicine. While platelet lysates have shown neuroprotective activity in preclinical models, the neurogenic potential of platelet concentrate-derived extracellular vesicles (pEVs) remains...
Platelet-derived materials are emerging as promising, cell-free biotherapies for regenerative medicine. While platelet lysates have shown neuroprotective activity in preclinical models, the neurogenic potential of platelet concentrate-derived extracellular vesicles (pEVs) remains underexplored. Here, we evaluated the effects of human pEVs and a neuroprotective heat-treated human platelet lysate (HPPL) on adult hippocampal neurogenesis using both an ex vivo neurosphere assay and an in vivo intranasal administration model. pEVs selectively enhanced dentate gyrus (DG)-derived neurosphere growth, even in the absence of exogenous growth factors, and were internalized by neural precursors. In vivo, short-term pEV delivery increased EdU proliferating cells in the DG, while long-term administration (28 days) elevated the proportion of newborn mature neurons. By contrast, HPPL primarily promoted early neurogenesis by expanding immature DCX neurons. Quantitative proteomics of DG tissue after pEV treatment revealed 111 differentially expressed proteins, with enrichment in pathways related to oxidative phosphorylation, Notch4 signaling, myelination, and MHC class I-mediated antigen presentation. Downregulated proteins included cytoskeletal and translation-related regulators, suggesting a shift toward neuronal differentiation and circuit integration. Biophysical characterization confirmed the purity and vesicular nature of pEVs, with a defined protein cargo including immune modulators and ECM-interacting molecules such as CD44, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1), and complement proteins. These findings identify allogeneic pEVs as multifunctional agents that modulate neural precursor cell fate and brain tissue remodeling through coordinated metabolic and immunoregulatory mechanisms. This work supports the translational potential of pEV-based therapeutics for promoting hippocampal neurogenesis and cognitive repair in neurodegenerative and age-related brain disorders.
Longevity Relevance Analysis
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Platelet concentrate-derived extracellular vesicles enhance adult hippocampal neurogenesis and promote cognitive repair. The study addresses mechanisms that could potentially counteract age-related cognitive decline, aligning with longevity research goals.
Jonalyn DeCastro, Ami Mehta-Doshi, Chao Liu ...
· Rejuvenation research
· Riggs School of Applied Life Sciences, Keck Graduate Institute, Claremont, California, USA.
· pubmed
Age-associated neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are marked by progressive degeneration of the nervous system. Current diagnostic approaches, such as neuroimaging and cerebrospinal fluid bioma...
Age-associated neurodegenerative diseases (NDDs), including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, are marked by progressive degeneration of the nervous system. Current diagnostic approaches, such as neuroimaging and cerebrospinal fluid biomarkers, are invasive, costly, and lack early diagnostic reliability. Recent studies highlight the potential of extracellular vesicles, particularly exosomes, derived from erythrocytes or red blood cells (RBCs), as emerging indicators of aging and age-associated diseases. Exosomes carry noncoding RNA, lipid, and protein molecules, and modulate cellular pathways at distant sites, providing neuroprotective and anti-inflammatory effects. In this study, we isolated RBC-derived exosomes of young and old mice. MicroRNA sequencing analysis revealed differential expression of several miRNA species between young and old mice. We report an upregulation of miR-125a-5p and a downregulation of miR-302a-5p in old mice that are potentially linked to neurodegenerative pathways. This study underscores the potential of RBC-derived exosomes as noninvasive biomarkers for NDDs.
Longevity Relevance Analysis
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The paper claims that RBC-derived exosomes exhibit differential microRNA expression linked to neurodegenerative pathways in aging. This research is relevant as it explores potential biomarkers for age-related neurodegeneration, addressing underlying mechanisms associated with aging rather than merely treating symptoms.
Fengli Xu, Haipeng Huang, Kun Peng ...
· Aging
· State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.
· pubmed
Reactive thiols of proteinaceous cysteines are vital to cell biology by serving as sensor, effector and buffer of environmental redox fluctuations. Being the major source, as well as the prime target, of reactive oxygen species (ROS), mitochondria confront great challenges in pre...
Reactive thiols of proteinaceous cysteines are vital to cell biology by serving as sensor, effector and buffer of environmental redox fluctuations. Being the major source, as well as the prime target, of reactive oxygen species (ROS), mitochondria confront great challenges in preserving their thiol pool. Here we show that ROS modulator 1 (ROMO1), a small inner mitochondrial membrane protein, plays a role in protecting the mitochondrial cysteinome. ROMO1 is redox sensitive and reactive and overexpression can prevent deleterious oxidation of proteinaceous thiols. ROMO1 upregulation leads to a reductive shift of the mitochondrial cysteinome, exerting beneficial effects on mitochondria, such as promoting energy metabolism and Ca
Longevity Relevance Analysis
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Overexpression of ROMO1 protects the mitochondrial cysteinome from oxidative damage, promoting mitochondrial health. The study addresses a mechanism related to mitochondrial function and oxidative stress, which are key factors in the aging process and longevity.
Kenna Brown, Ghazal Vahidi, Brady D Hislop ...
· Diet, High-Fat
· Department of Mechanical & Industrial Engineering, Montana State University, Bozeman, MT, USA.
· pubmed
The elderly are at increased risk of bone fracture and more often consume poor quality diets, such as high-fat diet (HFD). We hypothesized that HFD exacerbates the loss of bone fracture resistance in aging. Female and male 5-month and 22-month C57BL/6JN mice were fed moderate HFD...
The elderly are at increased risk of bone fracture and more often consume poor quality diets, such as high-fat diet (HFD). We hypothesized that HFD exacerbates the loss of bone fracture resistance in aging. Female and male 5-month and 22-month C57BL/6JN mice were fed moderate HFD (45%) or low-fat diet (10%) for 8 weeks. All HFD groups showed disrupted glucose metabolism. Aging and HFD lowered bone fracture toughness, while aging alone reduced bone strength. Raman Spectroscopy demonstrated that aging and HFD differently impact bone matrix. Aging altered matrix properties but the effect depended on sex. Both sexes had higher carbonate content and altered collagen structure (I1670/I1690) with age but males also had increased crystallinity. HFD decreased mineral maturity (i.e., crystallinity) as well as altered collagen structure in females but not males. Untargeted metabolomics revealed that cortical tissue metabolism was dysregulated with aging and HFD. Aging and HFD affected pathways related to cellular function and viability, or glucose regulation, respectively. In aging mice, HFD also impacted osteoclast and adipocyte abundance and osteocyte viability in both sexes. Together, these data demonstrate that HFD exacerbates the loss of bone matrix quality and fracture resistance in aging C57BL/6JN mice.
Longevity Relevance Analysis
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The paper claims that a short-term high-fat diet exacerbates the loss of bone matrix quality and fracture resistance in aging mice. This research is relevant as it explores the impact of diet on bone health in the context of aging, addressing potential root causes of age-related decline in bone integrity.
Jinhua Zhou, Xin Meng, Fan Wang ...
· Aging
· Department of Critical Care Medicine, The Third People's Hospital of Chengdu, Chengdu, 610031, China.
· pubmed
Biological Age Acceleration (BAA), as quantified by epigenetic clocks, is a well-established biomarker for mortality and age-related morbidity. This study aimed to investigate the independent and combined associations of sleep duration, sedentary behavior, and physical activity w...
Biological Age Acceleration (BAA), as quantified by epigenetic clocks, is a well-established biomarker for mortality and age-related morbidity. This study aimed to investigate the independent and combined associations of sleep duration, sedentary behavior, and physical activity with BAA risk.
Longevity Relevance Analysis
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The study investigates the associations between behavioral patterns and biological age acceleration. This paper is relevant as it explores factors that may influence the biological mechanisms of aging, contributing to our understanding of longevity and age-related health outcomes.
Anna Konturek-Ciesla, Qinyu Zhang, Shabnam Kharazi ...
· Lymphopoiesis
· Division of Molecular Hematology, Department of Laboratory Medicine, Lund Stem Cell Center, Medical Faculty, Lund University, Lund, Sweden.
· pubmed
Hematopoietic stem cell (HSC) transplantation offers a cure for a variety of blood disorders, predominantly affecting the elderly; however, its application, especially in this demographic, is limited by treatment toxicity. In response, we employ a murine transplantation model bas...
Hematopoietic stem cell (HSC) transplantation offers a cure for a variety of blood disorders, predominantly affecting the elderly; however, its application, especially in this demographic, is limited by treatment toxicity. In response, we employ a murine transplantation model based on low-intensity conditioning protocols using antibody-mediated HSC depletion. While aging presents a significant barrier to effective HSC engraftment, optimizing HSC doses and non-genotoxic targeting methods greatly enhance the long-term multilineage activity of the transplanted cells. We demonstrate that young HSCs, once effectively engrafted in aged hosts, improve hematopoietic output and ameliorate age-compromised lymphopoiesis. This culminated in a strategy that robustly mitigates disease progression in a genetic model of myelodysplastic syndrome. These results suggest that non-genotoxic HSC transplantation could fundamentally change the clinical management of age-associated hematological disorders, offering a prophylactic tool to delay or even prevent their onset in elderly patients.
Longevity Relevance Analysis
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The paper claims that non-genotoxic HSC transplantation can enhance lymphopoiesis and mitigate age-related blood diseases in mice. This research addresses the underlying challenges of aging in hematopoietic stem cell function, aiming to improve health outcomes in the elderly, which is directly relevant to longevity and age-related disease management.
Sabnam Sahin Rahman, Shreya Bhattacharjee, Simran Motwani ...
· Caenorhabditis elegans
· Molecular Aging Laboratory, BRIC-National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
· pubmed
The folate and methionine cycles (Met-C) are regulated by vitamin B12 (B12), obtained exclusively from diet and microbiota. Met-C supports amino acid, nucleotide, and lipid biosynthesis and provides one-carbon moieties for methylation reactions. While B12 deficiency and polymorph...
The folate and methionine cycles (Met-C) are regulated by vitamin B12 (B12), obtained exclusively from diet and microbiota. Met-C supports amino acid, nucleotide, and lipid biosynthesis and provides one-carbon moieties for methylation reactions. While B12 deficiency and polymorphisms in Met-C genes are clinically attributed to neurological and metabolic disorders, less is known about their cell-non-autonomous regulation of systemic physiological processes. Using a B12-sensitive Caenorhabditis elegans mutant, we show that the neuronal Met-C responds to differential B12 content in diet to regulate p38-MAPK activation in the intestine, thereby modulating cytoprotective gene expression, osmotic stress tolerance, behaviour and longevity. Mechanistically, our data suggest that B12-driven changes in the metabolic flux through the Met-C in the mutant's serotonergic neurons increase serotonin biosynthesis. Serotonin activates its receptor, MOD-1, in the post-synaptic interneurons, which then secretes the neuropeptide FLR-2. FLR-2 binding to its intestinal receptor, FSHR-1, induces the phase transition of the SARM domain protein TIR-1, thereby activating the p38-MAPK pathway. Together, we reveal a dynamic neuron-gut signalling axis that helps an organism modulate life history traits based on the status of neuronal Met-C, determined by B12 availability in its diet.
Longevity Relevance Analysis
(5)
The paper claims that the methionine cycle in serotonergic neurons regulates longevity through diet-dependent neuron-gut signaling. This research is relevant as it explores the underlying mechanisms of longevity and how dietary factors can influence lifespan through metabolic pathways.
Shinde, P. L., Kumar, V., Singh, S. ...
· pathology
· Rajiv Gandhi Centre for Biotechnology
· biorxiv
Biological aging and pressure overload-induced left ventricular cardiac hypertrophy (PO-CH) is marked by myocardial thickening, fibrosis, and functional decline, heightening the risk of heart failure. To advance therapeutic monitoring and intervention, we aimed to identify drug-r...
Biological aging and pressure overload-induced left ventricular cardiac hypertrophy (PO-CH) is marked by myocardial thickening, fibrosis, and functional decline, heightening the risk of heart failure. To advance therapeutic monitoring and intervention, we aimed to identify drug-responsive biomarkers with functional relevance to disease progression. Using rat models of biological aging (BA) and PO-CH, we evaluated the cardioprotective effects of Amalaki Rasayana (AR), a traditional nutraceutical, and its bioactive constituent gallic acid (GA), while concurrently profiling candidate serum biomarkers. Galectin-3 was present in full-length and oligomeric forms, with C-terminal (C-epitope) homo-oligomers closely associated with pathological remodeling. AR and GA significantly reduced these oligomers via cytoplasmic retention and phosphorylation-dependent downregulation of galectin-3 secretion, mitigating maladaptive cardiomyocyte signaling. Levels of atrial natriuretic peptide (ANP), cyclophilin A (PPIA), and albumin (ALB) showed consistent changes, reinforcing their utility as therapeutic response indicators. Findings were validated in sera from aged humans and patients responsive to clinical treatment, confirming translational potential. This study establishes a novel biomarker panel-galectin-3 C-epitope, ANP, PPIA, and ALB-for monitoring treatment efficacy and positions AR as a promising intervention in cardiac hypertrophy.
Longevity Relevance Analysis
(4)
The study identifies a panel of drug-responsive biomarkers for monitoring treatment efficacy in cardiac hypertrophy associated with aging. The research addresses a significant aspect of aging-related cardiac conditions, aiming to improve therapeutic interventions rather than merely treating symptoms.
Bae, H., Song, Z., Ali, A. ...
· genetics
· Oregon State University
· biorxiv
We constructed a polygenic protective score specific to Alzheimer\'s disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the US, Europe, and Asia. This AD PPS did not include variants on Apolip...
We constructed a polygenic protective score specific to Alzheimer\'s disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the US, Europe, and Asia. This AD PPS did not include variants on Apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial longevity. The current study also shows evidence that this genetic protection increases with increasingly older ages in centenarians (centenarians who died before reaching age 105 years, semi-supercentenarians who reached age 105 to 109 years, and supercentenarians who reached age 110 years and older). However, the genetic protection was of modest size: the average increase in AD PPS was approximately one additional protective allele per 5 years of gained lifetime. Additionally, we show that the higher AD PPS was associated with better cognitive function and decreased mortality. Taken together, this analysis suggests that individuals who achieve the most extreme ages, on average, have the greatest protection against AD. This finding is robust to different genetic backgrounds with important implications for universal applicability of therapeutics that target this AD PPS.
Longevity Relevance Analysis
(4)
Centenarians exhibit stronger genetic protection against Alzheimer's disease as they age, suggesting a link between longevity and genetic factors. The study focuses on genetic factors associated with extreme longevity and their implications for age-related diseases, aligning with the broader goals of longevity research.
Ayke Haller, Judith Risse, Bernice Sepers ...
· Molecular ecology resources
· Department of Animal Ecology, Netherlands Institute of Ecology (NIOO-KNAW), Wageningen, the Netherlands.
· pubmed
Information on individual age is a fundamental aspect in many ecological and evolutionary studies. However, accurate and non-lethal methods that can be applied to estimate the age of wild animals are often absent. Furthermore, since the process of ageing is accompanied by a physi...
Information on individual age is a fundamental aspect in many ecological and evolutionary studies. However, accurate and non-lethal methods that can be applied to estimate the age of wild animals are often absent. Furthermore, since the process of ageing is accompanied by a physical decline and the deterioration of biological functions, the biological age often deviates from the chronological age. Epigenetic marks are widely suggested to be associated with this age-related physical decline, and especially changes in DNA methylation are suggested to be reliable age-predictive biomarkers. Here, we developed separate epigenetic clocks for ageing and development in a small passerine bird, the great tit (Parus major). The ageing clock was constructed and evaluated using erythrocyte DNA methylation data of 122 post-fledging individuals, and the developmental clock using 67 pre-fledging individuals from a wild population. Using a leave-one-out cross-validation approach, we were able to accurately predict the ages of individuals with median absolute deviations of 0.40 years for the ageing and 1.06 days for the development clock. Moreover, using existing data from a brood-size manipulation, we show that nestlings from reduced broods are estimated to be biologically older compared to control nestlings, while they are expected to have higher fitness. These epigenetic clocks provide further evidence that, as observed in mammals, changes in DNA methylation of certain CpG sites are highly correlated with chronological age in birds and this opens up new avenues for broad applications in behavioural and evolutionary ecology.
Longevity Relevance Analysis
(4)
The paper claims that epigenetic clocks based on DNA methylation can accurately predict biological age in birds. This research is relevant as it explores biological aging mechanisms and provides insights that could inform broader ecological and evolutionary studies related to aging.
Myung Suk Rho, Kwang Pum Lee
· The Journal of experimental biology
· Department of Agricultural Biotechnology and Research Institute of Agriculture and Life Sciences, Seoul National University, 1 Gwanak-ro, Gwanak-gu, Seoul 08826, Republic of Korea.
· pubmed
Macronutrients profoundly affect both lifespan and reproduction and also modulate the fundamental trade-off between these two components of fitness in many insects. Beetles represent the largest group of insects, but nutritional interventions in lifespan and reproduction have nev...
Macronutrients profoundly affect both lifespan and reproduction and also modulate the fundamental trade-off between these two components of fitness in many insects. Beetles represent the largest group of insects, but nutritional interventions in lifespan and reproduction have never been thoroughly explored in this taxon. Here, we used nutritional landscape methodology to determine the effects of protein and carbohydrate intake on lifespan and reproduction in the mealworm beetle, Tenebrio molitor (Coleoptera: Tenebrionidae). The time of death and last reproduction, the number of eggs laid, and protein-carbohydrate intake were recorded from beetles maintained on one of 35 chemically defined foods varying in protein-to-carbohydrate ratio (P:C=0:1, 1:5, 1:2, 1:1, 2:1, 5:1, or 1:0) and in protein plus carbohydrate concentration (P+C=25.2, 33.6, 42, 50.4, or 58.8 %). Lifespan and reproductive traits increased with higher caloric intake, but their respective trait maxima occurred at different P:C ratios. Female reproductive traits peaked at higher P:C ratios (reproductive lifespan: 1:1.06; lifetime egg production: 1.31:1; egg production rate: 1.75:1) than those maximizing lifespan (male lifespan: 1:1.38; female lifespan: 1:1.36). This divergence indicates a nutrient-mediated trade-off between lifespan and reproduction in this species. Despite this, this nutritional conflict in T. molitor appeared to be less pronounced than what has been observed in other species commonly used in insect ageing research. When given a food choice, T. molitor beetles selected a P:C ratio close to 1:1, which simultaneously supported extended lifespan and high reproductive output.
Longevity Relevance Analysis
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The paper claims that macronutrient balance influences lifespan and reproduction in Tenebrio molitor. This research is relevant as it explores the nutritional factors that can affect lifespan, contributing to the understanding of aging mechanisms in a model organism.
Kevin Rhine, Rachel Li, Hema M Kopalle ...
· Nature neuroscience
· Department of Cellular & Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
· pubmed
Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts fro...
Aging is one of the most prominent risk factors for neurodegeneration, yet the molecular mechanisms underlying the deterioration of old neurons are mostly unknown. To efficiently study neurodegeneration in the context of aging, we transdifferentiated primary human fibroblasts from aged healthy donors directly into neurons, which retained their aging hallmarks, and we verified key findings in aged human and mouse brain tissue. Here we show that aged neurons are broadly depleted of RNA-binding proteins, especially spliceosome components. Intriguingly, splicing proteins-like the dementia- and ALS-associated protein TDP-43-mislocalize to the cytoplasm in aged neurons, which leads to widespread alternative splicing. Cytoplasmic spliceosome components are typically recruited to stress granules, but aged neurons suffer from chronic cellular stress that prevents this sequestration. We link chronic stress to the malfunctioning ubiquitylation machinery, poor HSP90α chaperone activity and the failure to respond to new stress events. Together, our data demonstrate that aging-linked deterioration of RNA biology is a key driver of poor resiliency in aged neurons.
Longevity Relevance Analysis
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Aged neurons exhibit mislocalization of splicing proteins leading to chronic cellular stress. This paper is relevant as it investigates the molecular mechanisms of neuronal aging, focusing on RNA biology deterioration as a potential root cause of neurodegeneration, rather than merely addressing symptoms.
Mayumi Shoji, Hisaya Kato, Masaya Koshizaka ...
· Aging cell
· Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, Chiba, Japan.
· pubmed
Werner syndrome (WS) is a rare hereditary progeroid syndrome caused by mutations in the WRN gene. Patients frequently develop various age-associated diseases prematurely, often leading to early mortality (≤ 60 years of age). Depletion of nicotinamide adenine dinucleotide (NAD)
Werner syndrome (WS) is a rare hereditary progeroid syndrome caused by mutations in the WRN gene. Patients frequently develop various age-associated diseases prematurely, often leading to early mortality (≤ 60 years of age). Depletion of nicotinamide adenine dinucleotide (NAD)
Longevity Relevance Analysis
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Nicotinamide riboside supplementation may improve health outcomes in patients with Werner syndrome. The study addresses a genetic condition that accelerates aging, focusing on a potential intervention that targets NAD+ levels, which is relevant to understanding and potentially mitigating aspects of aging.
Zorikova, E. O., Chourasia, S., Rosenhek-Goldian, I. ...
· biophysics
· Department of Immunology and Regenerative Biology, Weizmann Institute of Science
· biorxiv
Mitochondria play a pivotal role in energy production, signaling, and apoptosis. Yet, probing their functional state at the single-organelle level without invasive labels remains a major challenge. Here, we introduce a novel, label-free approach that leverages Atomic Force Micros...
Mitochondria play a pivotal role in energy production, signaling, and apoptosis. Yet, probing their functional state at the single-organelle level without invasive labels remains a major challenge. Here, we introduce a novel, label-free approach that leverages Atomic Force Microscopy (AFM) beyond its traditional imaging role, transforming it into a powerful tool for functional analysis of individual, isolated mitochondria. By immobilizing mouse liver mitochondria on polylysine-coated mica, we achieved nanoscale resolution of mitochondrial mechanical properties including height, height fluctuation power spectra, and Young\'s modulus, under different respiratory states. Strikingly, fluctuations in mitochondrial height fluctuations below 20 Hz showed robust correlation with the mitochondria membrane potential ({Delta}{psi}), a cornerstone of mitochondrial function. This relationship allows AFM to sensitively detect changes in the mitochondria bioenergetic status. Applying this method to mitochondria from liver-specific MTCH2 liver-conditional knockout mice, a model of mitochondrial malfunction, we confirmed AFM\'s diagnostic potential. The technique reliably distinguished malfunctional mitochondria, mirroring and adding new insights beyond conventional fluorescence assays. By bridging nanomechanics and mitochondrial bioenergetics, this approach paves the way for non-invasive, high-resolution diagnostics at the single-organelle level, holding promise to monitor the actual functional state of mitochondria in clinical settings.
Longevity Relevance Analysis
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The paper claims that a novel Atomic Force Microscopy technique can non-invasively analyze the mechanical properties of individual mitochondria, correlating these properties with mitochondrial membrane potential. This research is relevant as it addresses mitochondrial function, which is a critical aspect of cellular aging and longevity, potentially leading to insights into the root causes of age-related diseases.
Jiaxin Wen, Lingxian Yi, Lei Chen ...
· Stem cell research & therapy
· Senior Department of Orthopaedics, The Fourth Medical Centre, Chinese PLA General Hospital, Beijing, 100048, P.R. China.
· pubmed
Mesenchymal stem cells (MSCs) have potential for treating degenerative and immune diseases, but their clinical efficacy is limited by senescence, characterized by mitochondrial dysfunction, impaired mitophagy, and metabolic imbalance. The goal of this study was to investigate the...
Mesenchymal stem cells (MSCs) have potential for treating degenerative and immune diseases, but their clinical efficacy is limited by senescence, characterized by mitochondrial dysfunction, impaired mitophagy, and metabolic imbalance. The goal of this study was to investigate the effects of dimethyloxalylglycine (DMOG), a hypoxia-mimetic agent that stabilizes hypoxia-inducible factor 1 alpha (HIF-1α), on rejuvenating senescent MSCs by enhancing mitochondrial function, mitophagy, and metabolic reprogramming.
Longevity Relevance Analysis
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Short-term DMOG treatment enhances mitochondrial function and mitophagy in senescent mesenchymal stem cells. The paper addresses the rejuvenation of senescent cells, which is directly related to the underlying mechanisms of aging and potential lifespan extension.
Zijing Zhang, Lu Huang, Lynae Brayboy ...
· Biology of reproduction
· Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR.
· pubmed
The aging of mammalian ovary is accompanied by an increase in tissue fibrosis and heightened inflammation. Myeloid cells, including macrophages, monocytes, dendritic cells, and neutrophils, play pivotal roles in shaping the ovarian tissue microenvironment and regulating inflammat...
The aging of mammalian ovary is accompanied by an increase in tissue fibrosis and heightened inflammation. Myeloid cells, including macrophages, monocytes, dendritic cells, and neutrophils, play pivotal roles in shaping the ovarian tissue microenvironment and regulating inflammatory responses. However, a comprehensive understanding of the roles of these cells in the ovarian aging process is lacking. To bridge this knowledge gap, we utilized single-cell RNA sequencing (scRNAseq) and flow cytometry analysis to functionally characterize CD45+ CD11b+ myeloid cell populations in young (3 months old) and aged (14-17 months old) murine ovaries. Our dataset unveiled the presence of five ovarian macrophage subsets, including a Cx3cr1lowCd81hi subset unique to the aged murine ovary. Most notably, our data revealed significant alterations in ANNEXIN and TGFβ signaling within aged ovarian myeloid cells, which suggest a novel mechanism contributing to the onset and progression of aging-associated inflammation and fibrosis in the ovarian tissue.
Longevity Relevance Analysis
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The paper identifies age-associated changes in ovarian macrophages and signaling dynamics that contribute to inflammation and fibrosis in aging ovaries. This research is relevant as it explores the underlying mechanisms of aging-related changes in ovarian tissue, which could inform strategies for addressing age-related reproductive decline.
Jose Miguel Ramirez, Rogério Ribeiro, Oleksandra Soldatkina ...
· Genome medicine
· Department of Life Sciences, Barcelona Supercomputing Center (BSC), C/Jordi Girona 31, Barcelona, 08034, Spain.
· pubmed
Tobacco smoke is the main cause of preventable mortality worldwide. Smoking increases the risk of developing many diseases and has been proposed as an aging accelerator. Yet, the molecular mechanisms driving smoking-related health decline and aging acceleration in most tissues re...
Tobacco smoke is the main cause of preventable mortality worldwide. Smoking increases the risk of developing many diseases and has been proposed as an aging accelerator. Yet, the molecular mechanisms driving smoking-related health decline and aging acceleration in most tissues remain unexplored.
Longevity Relevance Analysis
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Cigarette smoking accelerates aging-related molecular changes across various tissues. The paper explores the molecular mechanisms linking smoking to aging, which is directly relevant to understanding the root causes of aging and age-related diseases.
Pooja Raj Devrukhkar, Mark A Watson, Bikem Soygur ...
· Aging cell
· Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
· pubmed
A major aging hallmark is the accumulation of cellular senescence burden. Over time, senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the senescence-associated secretory phenotype (SASP). The human ovary is one of the first or...
A major aging hallmark is the accumulation of cellular senescence burden. Over time, senescent cells contribute to tissue deterioration through chronic inflammation and fibrosis driven by the senescence-associated secretory phenotype (SASP). The human ovary is one of the first organs to age, and prominent age-related fibroinflammation within the ovarian microenvironment is consistent with the presence of senescent cells, but these cells have not been characterized in the human ovary. We thus established a doxorubicin-induced model of cellular senescence to establish a "senotype" (gene/protein signature of a senescence cell state) for ovarian senescent cells. Explants of human postmenopausal ovarian cortex and medulla were treated with doxorubicin for 24 h, followed by culture for up to 10 days in a doxorubicin-free medium. Tissue viability was confirmed by histology, lack of apoptosis, and continued glucose consumption by explants. Single nuclei sequencing and proteomics revealed an unbiased signature of ovarian senescence. We identified distinct senescence profiles for the cortex and medulla, driven predominantly by epithelial and stromal cells. Proteomics uncovered subregional differences in addition to 120 proteins common to the cortex and medulla SASP. Integration of transcriptomic and proteomic analyses revealed 26 shared markers, defining a senotype of doxorubicin-induced senescence unique to the postmenopausal ovary. A subset of these proteins: Lumican, SOD2, MYH9, and Periostin were mapped onto native tissue to reveal compartment-specific localization. This senotype will help determine the role of cellular senescence in ovarian aging, inform biomarker development to identify, and therapeutic applications to slow or reverse ovarian aging, senescence, and cancer.
Longevity Relevance Analysis
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The paper identifies a unique "senotype" of doxorubicin-induced cellular senescence in the postmenopausal human ovary. This research is relevant as it addresses the mechanisms of cellular senescence, a key factor in aging, and aims to inform therapeutic strategies to mitigate ovarian aging and its associated pathologies.
Qiuyan Wang, Yi Liang, Qingjuan Zuo ...
· Molecular and cellular biochemistry
· Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People's Republic of China.
· pubmed
Hypertension and its complications seriously affect human health, bringing about long-term medical burdens, functional impairments and even death. This study explored the impact of Canagliflozin (CANA) on the blood vessels of salt-sensitive hypertension. Male Dahl salt-sensitive ...
Hypertension and its complications seriously affect human health, bringing about long-term medical burdens, functional impairments and even death. This study explored the impact of Canagliflozin (CANA) on the blood vessels of salt-sensitive hypertension. Male Dahl salt-sensitive (Dahl SS) rats were fed with an 8% high-salt diet, and then intragastrically given CANA at a dose of 30 mg/kg/day or with a 0.5% hydroxypropyl methylcellulose solution for 12 weeks to induce hypertensive vascular damage and premature aging. Through vascular ultrasound detection, CANA improved the aortic stiffness and hemodynamics of high-salt-fed rats. Through vascular reactivity tests, CANA improved the carotid artery vasodilation. Hematoxylin and eosin (H&E), Sirius red, and senescence associated β-galactosidase staining were performed on the aorta, and CANA improved the fibrosis and aging of the aorta. CANA was found to reduce the expression of senescence associated secretory phenotype in the circulation that was induced by a high-salt diet. Additionally, it increased the expression of Sirtuin 6(SIRT6) in blood vessels and decreased the expression of Hypoxia-inducible factor 1α (HIF-1α) and its target genes. This study has demonstrated for the first time that CANA mitigates salt-induced aortic sclerosis and premature aging via the SIRT6/HIF-1α pathway.
Longevity Relevance Analysis
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Canagliflozin mitigates high-salt-induced aortic sclerosis and premature aging via the SIRT6/HIF-1α pathway. The study addresses mechanisms related to vascular aging and potential interventions that could influence longevity by targeting underlying pathways associated with aging.
Seung Eun Cha, Jieun Song, Steve Cole ...
· Health psychology : official journal of the Division of Health Psychology, American Psychological Association
· Department of Psychology, University of Wisconsin-Madison.
· pubmed
Cellular epigenetic aging has become an important marker of healthy or unhealthy aging. The current study examined whether lifelong cumulative stressors across multiple domains were linked with epigenetic age acceleration (EAA; i.e., epigenetic age greater than chronological age)...
Cellular epigenetic aging has become an important marker of healthy or unhealthy aging. The current study examined whether lifelong cumulative stressors across multiple domains were linked with epigenetic age acceleration (EAA; i.e., epigenetic age greater than chronological age) and whether psychological factors moderated this association. Dimensions of psychological well-being were hypothesized as protective factors, while neuroticism was posited as a vulnerability factor.
Longevity Relevance Analysis
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Lifelong cumulative stressors are linked with epigenetic age acceleration, moderated by psychological factors. The study addresses the relationship between stress and epigenetic aging, which is crucial for understanding the biological mechanisms of aging and potential interventions for longevity.
Connie J Mulligan
· Epigenomics
· Department of Anthropology, Genetics Institute, University of Florida, Gainesville, FL, USA.
· pubmed
The impact of psychosocial stress on mental and physical health is well-documented. Adverse experiences that occur early in life are particularly impactful on later life health. Epigenetic modifications, such as DNA methylation, have been proposed as a possible mechanism to media...
The impact of psychosocial stress on mental and physical health is well-documented. Adverse experiences that occur early in life are particularly impactful on later life health. Epigenetic modifications, such as DNA methylation, have been proposed as a possible mechanism to mediate the impact of childhood events on adult health outcomes. The development of epigenetic clocks to estimate epigenetic age has revealed many examples of epigenetic age acceleration (and deceleration) in association with exposure to psychosocial stressors. Furthermore, altered epigenetic aging has been associated with downstream health outcomes. Here studies are discussed that have reported associations of epigenetic aging with early-life exposure to psychosocial stressors, such as childhood abuse and neglect, and with later-life health outcomes, including increased mortality, morbidity, and disease risk. Protective factors that may mitigate the effect of psychosocial stress on epigenetic aging, and possibly enable reversal of epigenetic aging, are also discussed.
Longevity Relevance Analysis
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The paper discusses the association between epigenetic age acceleration due to psychosocial stressors in early childhood and later-life health outcomes. This research is relevant as it explores the underlying mechanisms of aging and how early-life experiences can influence biological aging processes, potentially informing interventions for age-related diseases.
Birgit Kastberger, Anupam Sah, Simone B Sartori ...
· Journal of dietary supplements
· EVER Neuro Pharma, Unterach am Attersee, Austria.
· pubmed
This study investigates the effects of N‑PEP‑12, a neuroprotective dietary supplement, on cognitive function, neuroplasticity, and neurogenesis in aged 129S1/SvImJ (S1) mice, which are known for age‑associated cognitive impairments. The primary objective was to determine whether ...
This study investigates the effects of N‑PEP‑12, a neuroprotective dietary supplement, on cognitive function, neuroplasticity, and neurogenesis in aged 129S1/SvImJ (S1) mice, which are known for age‑associated cognitive impairments. The primary objective was to determine whether N‑PEP‑12 could improve memory retention and enhance neural health by modulating hippocampal plasticity and neurogenesis. S1 mice were chronically treated with N‑PEP‑12 or a Vehicle to assess its impact on cognitive performance using cued fear conditioning (CFC) and object location memory (OLM) tests. Additionally, in vitro studies examined the effects of N‑PEP‑12 on neuroplasticity markers such as Neurofilament Light Chain (NF‑L) expression and vasopressin (AVP) promoter methylation, to elucidate the molecular mechanisms underlying cognitive enhancements. N‑PEP‑12 treatment significantly improved associative and contextual memory in the CFC and OLM tests respectively. In vitro assays revealed that N‑PEP‑12 increased NF‑L expression and decreased AVP promoter methylation, indicating enhanced neuroplasticity and neurogenesis. Furthermore, N‑PEP‑12 preserved blood‑brain barrier integrity under oxidative stress conditions, suggesting a protective role against vascular‑related cognitive decline. The findings suggest that N‑PEP‑12 promotes hippocampal health by enhancing neurogenesis and neuroplasticity, potentially mitigating age‑related cognitive decline. These results highlight N‑PEP‑12 as a promising agent for supporting healthy cognitive function in aging populations through the modulation of neurobiological pathways associated with learning and memory.
Longevity Relevance Analysis
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N-PEP-12 improves cognitive function and enhances neuroplasticity and neurogenesis in aged mice. The paper is relevant as it investigates a potential intervention that targets mechanisms associated with cognitive decline in aging, addressing underlying biological processes rather than merely treating symptoms.
Faranak Elmi, Fatemeh Soltanmohammadi, Tahura Fayeghi ...
· Regenerative therapy
· Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
· pubmed
The efficacy of mesenchymal stem cells (MSCs) mediated regenerative therapies has been hindered by the senescence of them during long period cultures. Aged MSCs exhibit altered morphology, decreased stemmas, changed intercellular communication, and poor differentiation ability. B...
The efficacy of mesenchymal stem cells (MSCs) mediated regenerative therapies has been hindered by the senescence of them during long period cultures. Aged MSCs exhibit altered morphology, decreased stemmas, changed intercellular communication, and poor differentiation ability. Besides in physiological condition, upon transplantation of senescent MSCs, they are capable of activating both the innate and adaptive immune systems, playing a crucial role in preserving tissue homeostasis. Therefore, enhancing immunomodulation properties and preventing aging progress of MSCs to achieve successful future clinical applications seems necessary. This review delves into the current knowledge of the underlying cellular and molecular mechanisms that promote MSCs senescence as well as the developed approaches for reversing or preventing MSCs aging. These include pre-treatment of MSCs with various types of molecules to inhibit aging process and implementation of different types of three-dimensional culture systems. In addition, the recently developed strategies to improve immunomodulatory properties of MSCs have been discussed. By addressing the limitations of aged MSCs and augmenting their immunomodulation, these approaches offer a promising avenue for the future of cell therapy and provide valuable tools for maximizing the effectiveness of MSCs therapy in biomedical applications.
Longevity Relevance Analysis
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The paper discusses strategies to prevent MSC aging and enhance their immunomodulatory properties for improved cell-based therapies. This is relevant as it addresses the mechanisms of aging in MSCs, which is crucial for developing therapies that could mitigate age-related decline in regenerative capacity.
Athanase Benetos, Coralie Fritsch, Emma Horton ...
· Telomerase
· Université de Lorraine, Inserm, DCAC, Nancy, F-54000, France.
· pubmed
Telomeres are repetitive sequences of nucleotides at the end of chromosomes, whose evolution over time is intrinsically related to biological ageing. In most cells, with each cell division, telomeres shorten due to the so-called end replication problem, which can lead to replicat...
Telomeres are repetitive sequences of nucleotides at the end of chromosomes, whose evolution over time is intrinsically related to biological ageing. In most cells, with each cell division, telomeres shorten due to the so-called end replication problem, which can lead to replicative senescence and a variety of age-related diseases. On the other hand, in certain cells, the presence of the enzyme telomerase can lead to the lengthening of telomeres, which may delay or prevent the onset of such diseases but can also increase the risk of cancer. In this article, we propose a stochastic representation of this biological model, which takes into account multiple chromosomes per cell, the effect of telomerase, different cell types and the dependence of the distribution of telomere length on the dynamics of the process. We study theoretical properties of this model, including its long-term behaviour. In addition, we investigate numerically the impact of the model parameters on biologically relevant quantities, such as the Hayflick limit and the Malthusian parameter of the population of cells.
Longevity Relevance Analysis
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The paper proposes a stochastic model to analyze telomere dynamics influenced by telomerase activity. This research is relevant as it addresses the biological mechanisms underlying telomere shortening and its implications for aging and age-related diseases, potentially contributing to understanding longevity.
Jamie L Arnst, Uma D Alappan, Manjula Viggeswarapu ...
· GeroScience
· The Atlanta Department of Veterans Affairs Medical Center, Decatur, GA, 30033, USA.
· pubmed
The loss of bone volume during aging is common in both men and women and can have substantial negative health impacts. Weakened bones can lead to fractures which in turn can result in hospitalization, decreased quality of life, and early death. The post-diagnosis treatment of ost...
The loss of bone volume during aging is common in both men and women and can have substantial negative health impacts. Weakened bones can lead to fractures which in turn can result in hospitalization, decreased quality of life, and early death. The post-diagnosis treatment of osteoporosis has received the bulk of attention with less research focused on prevention and modifiable risk factors such as nutrition. Calcium and vitamin D supplementation has provided limited skeletal benefit in healthy individuals and there is no currently sufficient information on other components of the diet for informed dietary choices related to bone health. Inorganic phosphate (Pi) is a dietary element that is consumed in excess in most Western diets and has been suggested to strongly influence bone metabolism. However, how duration of dietary Pi choices, stage of life, and gender influence the impact on long-term bone health is lacking. To address these issues, young (10 week) and old (82 week) male mice were fed low, normal, or high Pi content diets with calcium kept constant at 0.6% for 10 weeks and bone indices and Pi-responsive serum factors were measured. To determine if changes in bone quality in response to changes in dietary Pi were chronic or could be reversed, additional groups of mice were fed low or high Pi diets for 10 weeks and switched back to normal Pi for the final 10 weeks. A low-Pi additive diet produced a significant increase in trabecular and cortical bone volume in both young and old male mice. The high Pi diet generated trabecular bone loss in young mice which was not reversible by switching back to a normal Pi diet. The high Pi diet also induced accelerated loss of cortical bone and kidney calcification in old mice. Taken together, the results suggest that dietary choices made early in life could have long-term consequences on bone health and identify a novel non-pharmacologic, modifiable nutritional choice, in a low-Pi additive diet that could be used to build bone mass and/or prevent bone loss in the elderly.
Longevity Relevance Analysis
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Dietary phosphate intake significantly influences bone metabolism and health during aging. The study addresses modifiable dietary factors that can impact bone health, which is a critical aspect of longevity and age-related diseases.
Kriz, A. J., Mao, S., Shao, D. D. ...
· genomics
· Boston Children\'s Hospital
· biorxiv
Elucidating the role of somatic mutations in cancer, healthy tissues, and aging depends on methods that can accurately characterize somatic mosaicism across different cell types, as well as assay their impact on cellular function. Current technologies to study cell-type-specific ...
Elucidating the role of somatic mutations in cancer, healthy tissues, and aging depends on methods that can accurately characterize somatic mosaicism across different cell types, as well as assay their impact on cellular function. Current technologies to study cell-type-specific somatic mutations within tissues are low-throughput. We developed Duplex-Multiome, incorporating duplex consensus sequencing to accurately identify somatic single-nucleotide variants (sSNV) from the same nucleus simultaneously analyzed for single-nucleus ATAC-seq (snATAC-seq) and RNA-seq (snRNA-seq). By introducing strand-tagging into the construction of snATAC-seq libraries, duplex sequencing reduces sequencing error by >10,000-fold while eliminating artifactual mutational signatures. When applied to 98%/2% mixed cell lines, Duplex-Multiome identified sSNVs present in 2% of cells with 92% precision and accurately captured known sSNV mutational spectra, while revealing unexpected subclonal lineages. Duplex-Multiome of > 51,400 nuclei from postmortem brain tissue captured sSNV burdens and spectra across all major brain cell types and subtypes, including those difficult to assay by single-cell whole-genome sequencing (scWGS). This revealed for the first time that diverse neuronal and glial cell types show distinct rates and patterns of age-related mutation, while also directly discovering developmental cell lineage relationships. Duplex-Multiome identified clonal sSNVs occurring at increased rates in glia of certain aged brains, as well as clonal sSNVs that correlated with changes in expression of nearby genes, in both neurotypical and autism spectrum disorder (ASD) individuals, directly demonstrating that somatic mutagenesis can contribute to gene expression phenotypes. Duplex-Multiome can be easily adopted into the 10X Multiome protocol and will bridge somatic mosaicism to a wide range of phenotypic readouts across cell types and tissues.
Longevity Relevance Analysis
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The paper claims that somatic mutations in diverse neuronal and glial cell types show distinct rates and patterns of age-related mutation, which can contribute to gene expression phenotypes. This research addresses the underlying mechanisms of somatic mutations in the aging brain, providing insights into the biological processes that may contribute to aging and age-related diseases.
Bai, Y., Yuan, T., Ren, L. ...
· genetics
· Peking University
· biorxiv
DNA methylation dynamics, including 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC), critically regulate brain function, yet conventional methods cannot distinguish these modifications, obscuring their distinct roles in gene regulation and aging. We present Joint-Cabern...
DNA methylation dynamics, including 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC), critically regulate brain function, yet conventional methods cannot distinguish these modifications, obscuring their distinct roles in gene regulation and aging. We present Joint-Cabernet, a bisulfite-free single-cell platform enabling simultaneous profiling of 5hmC, 5mC, and transcriptomes. Applying Joint-Cabernet to 84,071 nuclei from adult and aged mouse brains, we resolved cell-type-specific DNA hydroxymethylation landscapes, revealing elevated 5hmCG and 5hmCH levels in transcriptionally active genes across neuronal subtypes and spatial gradients in cortical layers. During aging, 5hmCG accumulates globally but is selectively enriched at open chromatin loci, aligning with the upregulation of cell-type-specific genes in distinct brain cell types. This single-cell DNA methylation brain cell atlas provides a framework for studying methylation-driven mechanisms in brain aging and neurodegenerative diseases.
Longevity Relevance Analysis
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The paper claims that aging leads to selective enrichment of DNA hydroxymethylation at open chromatin loci in specific brain cell types. This research is relevant as it explores the molecular mechanisms of aging in the brain, potentially uncovering insights into the root causes of age-related cognitive decline and neurodegenerative diseases.
Yang, L., Lin, S., Tao, Y. ...
· bioinformatics
· University of Nottingham Ningbo China
· biorxiv
Single-cell RNA sequencing (scRNA-seq) has significantly advanced our understanding of retinal aging, yet the specific molecular characteristics within cell populations remain incompletely defined. We profiled 223,612 single cells from 18 unfrozen human retinas obtained from 13 C...
Single-cell RNA sequencing (scRNA-seq) has significantly advanced our understanding of retinal aging, yet the specific molecular characteristics within cell populations remain incompletely defined. We profiled 223,612 single cells from 18 unfrozen human retinas obtained from 13 Chinese donors aged 34-92 years, providing an ethnically specific atlas across the adult lifespan. A sparsity-driven machine-learning (ML) pipeline (L1-regularized logistic regression, recursive feature elimination with cross-validation) identified age-discriminatory genes within each major retinal cell type, complemented by gene set scoring for cellular senescence and metabolic pathways. Using integrated differential expression and ML feature selection, we identified eleven major retinal cell populations and observed aging-associated shifts. ML classifiers achieved high accuracy (80-96%), particularly for microglia (96%), revealing mitochondria-centric aging signatures in rods and bipolar cells, proteostasis and retinoid metabolism in cones, and structural-RNA maintenance signatures in horizontal cells. This study delivers the first ML-derived, cell-type-specific aging gene signatures for the human retina in a Chinese cohort, offering a reference for population-tailored biomarker discovery.
Longevity Relevance Analysis
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The study identifies age-discriminatory gene signatures in specific retinal cell types using machine learning. This research is relevant as it explores the molecular characteristics of aging at a cellular level, contributing to the understanding of the biological mechanisms underlying aging.
Wang, J., Cai, Z., Gu, J. ...
· physiology
· Hunan Normal University
· biorxiv
Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes critical for physiological homeostasis and organismal ageing. While mTORC1 preferentially regulates the translation of 5\'-terminal oligopyrimidine (TOP) motif-conta...
Mechanistic target of rapamycin complex 1 (mTORC1) senses nutrient availability to orchestrate metabolic processes critical for physiological homeostasis and organismal ageing. While mTORC1 preferentially regulates the translation of 5\'-terminal oligopyrimidine (TOP) motif-containing mRNAs that predominantly encode ribosomal proteins (RPs) via the translational repressor 4E-BP, this mTORC1 function is resistant to rapamycin inhibition. TOP mRNAs are exceptionally abundant, thus imposing a major translational burden on cells; yet how their translation is physiologically tuned and linked to longevity remain unexplored. Here we identify Lsp2, originally known as a storage protein, as an adipose effector of mTORC1 that modulates lifespan in Drosophila. Lsp2 is induced by essential amino acids (EAAs) via mTORC1. Genetic ablation of Lsp2 to blunt organismal response to protein diets drives robust lifespan extension without compromising key life-history traits such as reproduction. Translatomic profiling reveals that loss of Lsp2 selectively reduces global TOP mRNA translation in a 4E-BP-dependent manner, thereby extending lifespan via a mechanism distinct from rapamycin inhibition that fails to reduce 4E-BP phosphorylation in vivo. Finally, Lsp2 adipokine promotes 4E-BP phosphorylation and acts systemically across tissues to shape the lifespan responses to dietary protein. Collectively, our findings establish Lsp2 as a novel translational regulator of TOP genes that mechanistically couples physiological ribosomal protein synthesis with organismal longevity.
Longevity Relevance Analysis
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The paper claims that the adipose mTORC1 effector Lsp2 modulates lifespan in Drosophila by regulating the translation of TOP mRNAs. This research is relevant as it explores a mechanism linking nutrient sensing and ribosomal protein synthesis to longevity, addressing fundamental aspects of aging biology.
Hushpulian, D. M., Ammal Kaidery, N., Soni, P. ...
· biochemistry
· Department of Pediatrics, Darby Childrens Research Institute, Department of Neuroscience, Department of Drug Discovery, Medical University of South Carolina, Ch
· biorxiv
Activating Nrf2 with small molecules is a promising strategy for countering aging, oxidative stress, inflammation, and various disorders, including neurodegeneration. The primary regulator of Nrf2 protein stability is Keap1, a redox sensor protein and an adapter in the Cullin III...
Activating Nrf2 with small molecules is a promising strategy for countering aging, oxidative stress, inflammation, and various disorders, including neurodegeneration. The primary regulator of Nrf2 protein stability is Keap1, a redox sensor protein and an adapter in the Cullin III ubiquitin ligase complex, which labels Nrf2 for proteasomal degradation. The known Nrf2 activators either chemically modify sensor thiols in Keap1 or competitively displace Nrf2 from the ubiquitin ligase complex. The latter approach is considered the most suitable for continuous administration, as non-specific chemical modifiers of Keap1 thiols also modify active thiols on other proteins, thus causing side effects. However, when transitioning from homogeneous to cell-based assays, genuine displacement activators show a significant loss in potency by several orders of magnitude. As we demonstrate here, this offset is due to the presence of high micromolar concentrations of Keap1 in both the cell lines and brain tissue. A potential solution could involve targeted delivery of an alkylating agent to Keap1 to achieve the desired specificity. Transcriptomic analysis of a cell-permeable Nrf2 peptide bearing an alkylating fumarate moiety indicates selective activation of the Nrf2 genetic program, confirming the high specificity of this approach. The Nrf2-triggered genetic program has a feedback regulation mechanism through the activation of Bach1, an Nrf2 transcriptional repressor, which is elevated in age-related neurodegeneration. Thus, a benign bipartite Nrf2 activator with Bach1 inhibition properties is needed for maximal benefits. The recently developed heterocyclic carboxamide, HPPE, shows overlap with the Nrf2 pathway activated by the fumarate-linked Nrf2 peptide and with zinc and tin protoporphyrins, which are recognized inhibitors of Bach1. Therefore, HPPE presents a promising and unique combination of the two desired activities that could be further optimized to treat age-related neurodegeneration.
Longevity Relevance Analysis
(4)
The paper claims that a bipartite Nrf2 activator with Bach1 inhibition properties can effectively target age-related neurodegeneration. This research addresses mechanisms related to oxidative stress and inflammation, which are fundamental aspects of aging and age-related diseases, rather than merely treating symptoms.
Guan, C., Ryu, S., Dong, M. ...
· immunology
· Yale School of Medicine
· biorxiv
Taurine, the most abundant sulfonic amino acid in humans is largely obtained from diets rich in animal proteins. However, taurine is dietary non-essential because it can be synthesized from cysteine by activation of transsulfuration pathway (TSP) when food consumption is low or i...
Taurine, the most abundant sulfonic amino acid in humans is largely obtained from diets rich in animal proteins. However, taurine is dietary non-essential because it can be synthesized from cysteine by activation of transsulfuration pathway (TSP) when food consumption is low or if the diet is predominantly plant based. The decline of taurine was proposed as the driver of aging through an undefined mechanism. Here, we found that mild food restriction in humans for one year that resulted in 14% reduction of calorie intake elevated the hypotaurine and taurine concentration in adipose tissue. Therefore, we investigated whether elevated taurine mimics beneficial effects of caloric restriction on inflammation, a key mechanism of aging. Interestingly, aging increased the circulating and tissue concentrations of taurine suggesting that elevated taurine may serve as a hormetic stress response metabolite that regulates mechanism of age-related inflammation. The elevated taurine protected mice against mortality from sepsis and inhibited inflammasome-driven inflammation and gasdermin-D (GSDMD) mediated pyroptosis. Mechanistically, danger signals including hypotonicity that activate NLRP3-inflammasome, caused upstream taurine efflux from macrophages, which triggered potassium (K+) release and downstream canonical NLRP3 inflammasome assembly, caspase-1 activation, GSDMD cleavage and IL-1{beta} and IL-18 secretion that was reversed by taurine restoration. Notably, taurine does not efflux from GSDMD pore and inhibited IL-1{beta} from macrophages independently of known transporters SLC6A6 and SLC36A1. Increased taurine in old mice promotes healthspan by inducing anti-inflammatory pathways previously linked to youthfulness. These findings demonstrate that taurine is an upstream metabolic sensor of cellular perturbations that control NLRP3 inflammasome and lowers age-related inflammation.
Longevity Relevance Analysis
(4)
Elevated taurine levels can mimic the beneficial effects of caloric restriction by inhibiting age-related inflammation through the deactivation of the NLRP3 inflammasome. This paper is relevant as it explores a potential mechanism that addresses inflammation, a key factor in the aging process, and suggests a metabolic intervention that could influence longevity.